5-substituted quinazolinone derivatives and compositions comprising and methods of using the same

ABSTRACT

Provided are 5-substituted quinazolinone compounds, for example, of formula (I), and pharmaceutically acceptable salts, solvates, clathrates, stereoisomers, and prodrugs thereof. Methods of use for treating angiogenesis or cytokine related disorders, and pharmaceutical compositions of these compounds are disclosed.

1. CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Application No.60/847,471, filed Sep. 26, 2006, the entirety of which is incorporatedherein by reference.

2. FIELD OF THE INVENTION

Provided herein are 5-substituted quinzolinone derivatives.Pharmaceutical compositions comprising the compounds and methods fortreating, preventing and managing various disorders are also disclosed.

3. BACKGROUND OF THE INVENTION 3.1 Pathobiology of Cancer and OtherDiseases

Cancer is characterized primarily by an increase in the number ofabnormal cells derived from a given normal tissue, invasion of adjacenttissues by these abnormal cells, or lymphatic or blood-borne spread ofmalignant cells to regional lymph nodes and to distant sites(metastasis). Clinical data and molecular biologic studies indicate thatcancer is a multistep process that begins with minor preneoplasticchanges, which may under certain conditions progress to neoplasia. Theneoplastic lesion may evolve clonally and develop an increasing capacityfor invasion, growth, metastasis, and heterogeneity, especially underconditions in which the neoplastic cells escape the host's immunesurveillance. Roitt, I., Brostoff, J and Kale, D., Immunology,17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).

There is an enormous variety of cancers which are described in detail inthe medical literature. Examples includes cancer of the lung, colon,rectum, prostate, breast, brain, and intestine. The incidence of cancercontinues to climb as the general population ages, as new cancersdevelop, and as susceptible populations (e.g., people infected with AIDSor excessively exposed to sunlight) grow. However, options for thetreatment of cancer are limited. For example, in the case of bloodcancers (e.g., multiple myeloma), few treatment options are available,especially when conventional chemotherapy fails and bone-marrowtransplantation is not an option. A tremendous demand therefore existsfor new methods and compositions that can be used to treat patients withcancer.

Many types of cancers are associated with new blood vessel formation, aprocess known as angiogenesis. Several of the mechanisms involved intumor-induced angiogenesis have been elucidated. The most direct ofthese mechanisms is the secretion by the tumor cells of cytokines withangiogenic properties. Examples of these cytokines include acidic andbasic fibroblastic growth factor (a,b-FGF), angiogenin, vascularendothelial growth factor (VEGF), and TNF-α. Alternatively, tumor cellscan release angiogenic peptides through the production of proteases andthe subsequent breakdown of the extracellular matrix where somecytokines are stored (e.g., b-FGF). Angiogenesis can also be inducedindirectly through the recruitment of inflammatory cells (particularlymacrophages) and their subsequent release of angiogenic cytokines (e.g.,TNF-α, b-FGF).

A variety of other diseases and disorders are also associated with, orcharacterized by, undesired angiogenesis. For example, enhanced orunregulated angiogenesis has been implicated in a number of diseases andmedical conditions including, but not limited to, ocular neovasculardiseases, choroidal neovascular diseases, retina neovascular diseases,rubeosis (neovascularization of the angle), viral diseases, geneticdiseases, inflammatory diseases, allergic diseases, and autoimmunediseases. Examples of such diseases and conditions include, but are notlimited to: diabetic retinopathy; retinopathy of prematurity; cornealgraft rejection; neovascular glaucoma; retrolental fibroplasia;arthritis; and proliferative vitreoretinopathy.

Accordingly, compounds that can control angiogenesis or inhibit theproduction of certain cytokines, including TNFα, may be useful in thetreatment and prevention of various diseases and conditions.

3.2 Methods of Treating Cancer

Current cancer therapy may involve surgery, chemotherapy, hormonaltherapy and/or radiation treatment to eradicate neoplastic cells in apatient (see, e.g., Stockdale, 1998, Medicine, vol. 3, Rubenstein andFederman, eds., Chapter 12, Section IV). Recently, cancer therapy couldalso involve biological therapy or immunotherapy. All of theseapproaches pose significant drawbacks for the patient. Surgery, forexample, may be contraindicated due to the health of a patient or may beunacceptable to the patient. Additionally, surgery may not completelyremove neoplastic tissue. Radiation therapy is only effective when theneoplastic tissue exhibits a higher sensitivity to radiation than normaltissue. Radiation therapy can also often elicit serious side effects.Hormonal therapy is rarely given as a single agent. Although hormonaltherapy can be effective, it is often used to prevent or delayrecurrence of cancer after other treatments have removed the majority ofcancer cells. Biological therapies and immunotherapies are limited innumber and may produce side effects such as rashes or swellings,flu-like symptoms, including fever, chills and fatigue, digestive tractproblems or allergic reactions.

With respect to chemotherapy, there are a variety of chemotherapeuticagents available for treatment of cancer. A majority of cancerchemotherapeutics act by inhibiting DNA synthesis, either directly, orindirectly by inhibiting the biosynthesis of deoxyribonucleotidetriphosphate precursors, to prevent DNA replication and concomitant celldivision. Gilman et al., Goodman and Gilman's: The Pharmacological Basisof Therapeutics, Tenth Ed. (McGraw Hill, New York).

Despite availability of a variety of chemotherapeutic agents,chemotherapy has many drawbacks. Stockdale, Medicine, vol. 3, Rubensteinand Federman, eds., ch. 12, sect. 10, 1998. Almost all chemotherapeuticagents are toxic, and chemotherapy causes significant, and oftendangerous side effects including severe nausea, bone marrow depression,and immunosuppression. Additionally, even with administration ofcombinations of chemotherapeutic agents, many tumor cells are resistantor develop resistance to the chemotherapeutic agents. In fact, thosecells resistant to the particular chemotherapeutic agents used in thetreatment protocol often prove to be resistant to other drugs, even ifthose agents act by different mechanism from those of the drugs used inthe specific treatment. This phenomenon is referred to as pleiotropicdrug or multidrug resistance. Because of the drug resistance, manycancers prove or become refractory to standard chemotherapeutictreatment protocols.

Other diseases or conditions associated with, or characterized by,undesired angiogenesis are also difficult to treat. However, somecompounds such as protamine, hepain and steroids have been proposed tobe useful in the treatment of certain specific diseases. Taylor et al.,Nature 297:307 (1982); Folkman et al., Science 221:719 (1983); and U.S.Pat. Nos. 5,001,116 and 4,994,443.

Still, there is a significant need for safe and effective methods oftreating, preventing and managing cancer and other diseases andconditions, including for diseases that are refractory to standardtreatments, such as surgery, radiation therapy, chemotherapy andhormonal therapy, while reducing or avoiding the toxicities and/or sideeffects associated with the conventional therapies.

4. SUMMARY OF THE INVENTION

Provided herein are 5-substituted quinazolinone compounds, andpharmaceutically acceptable salts, solvates (e.g., hydrates), prodrugs,clathrates, or stereoisomers thereof.

Also provided are methods of treating and managing various diseases ordisorders. The methods comprise administering to a patient in need ofsuch treatment or management a therapeutically effective amount of acompound provided herein, or a pharmaceutically acceptable salt,solvate, prodrug, clathrate, or stereoisomer thereof.

Also provided herein are methods of preventing various diseases anddisorders, which comprise administering to a patient in need of suchprevention a prophylactically effective amount of a compound providedherein, or a pharmaceutically acceptable salt, solvate, prodrug,clathrate, or stereoisomer thereof.

Also provided herein are pharmaceutical compositions, single unit dosageforms, dosing regimens and kits which comprise a compound providedherein, or a pharmaceutically acceptable salt, solvate, prodrug,clathrate, or stereoisomer thereof.

5. DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, provided are 5-substituted quinazolinone compounds,and pharmaceutically acceptable salts, solvates, prodrugs, clathrate,and stereoisomers thereof.

In another embodiment, provided are methods of treating, managing, andpreventing various diseases and disorders, which comprises administeringto a patient in need of such treatment or prevention a therapeuticallyor prophylactically effective amount of a compound provided herein, or apharmaceutically acceptable salt, solvate, prodrug, clathrate, orstereoisomer thereof. Examples of diseases and disorders are describedherein.

In other embodiments, a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, prodrug, clathrate, or stereoisomer thereof,is administered in combination with another drug (“second active agent”)or treatment. Second active agents include small molecules and largemolecules (e.g., proteins and antibodies), examples of which areprovided herein, as well as stem cells. Methods, or therapies, that canbe used in combination with the administration of compounds providedherein include, but are not limited to, surgery, blood transfusions,immunotherapy, biological therapy, radiation therapy, and other non-drugbased therapies presently used to treat, prevent or manage variousdisorders described herein.

Also provided are pharmaceutical compositions (e.g., single unit dosageforms) that can be used in the methods provided herein. In oneembodiment, pharmaceutical compositions comprise a compound providedherein, or a pharmaceutically acceptable salt, solvate, prodrug,clathrate, or stereoisomer thereof, and optionally a second activeagent.

5.1 Compounds

In one embodiment, provided herein are compounds of the formula (I):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R¹ is: hydrogen; halo; —(CH₂)₂OH; (C₁-C₆)alkyl, optionally    substituted with one or more halo; (C₁-C₆)alkoxy, optionally    substituted with one or more halo; or    -   —(CH₂)_(n)NHR^(a), wherein R^(a) is:        -   hydrogen;        -   (C₁-C₆)alkyl, optionally substituted with one or more halo;        -   —(CH₂)_(n)-(6 to 10 membered aryl);        -   —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or            —C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the            aryl or heteroaryl is optionally substituted with one or            more of: halo; —SCF₃; (C₁-C₆)alkyl, itself optionally            substituted with one or more halo; or (C₁-C₆)alkoxy, itself            optionally substituted with one or more halo;        -   —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionally            substituted with one or more halo;        -   —C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl);        -   —C(O)—(CH₂)_(n)—NR^(b)R^(c), wherein R^(b) and R^(c) are            each independently:            -   hydrogen;            -   (C₁-C₆)alkyl, optionally substituted with one or more                halo;            -   (C₁-C₆)alkoxy, optionally substituted with one or more                halo; or            -   6 to 10 membered aryl, optionally substituted with one                or more of: halo; (C₁-C₆)alkyl, itself optionally                substituted with one or more halo; or (C₁-C₆)alkoxy,                itself optionally substituted with one or more halo;        -   —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl; or        -   —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10 membered aryl);-   R² is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo;-   R³ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one or    more halo; and-   n is 0, 1, or 2.

In one embodiment, provided herein are compounds of the formula (II):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R⁴ is: hydrogen; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyl, optionally    substituted with one or more halo; or (C₁-C₆)alkoxy, optionally    substituted with one or more halo;-   R⁵ is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo;-   R⁶ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one or    more halo; and-   n is 0, 1, or 2.

In one embodiment, R⁴ is hydrogen. In another embodiment, R⁴ is halo. Inanother embodiment, R⁴ is (C₁-C₆)alkyl, optionally substituted with oneor more halo. In another embodiment, R⁴ is —(CH₂)_(n)OH or hydroxyl. Inanother embodiment, R⁴ is (C₁-C₆)alkoxy, optionally substituted with oneor more halo.

In one embodiment, R⁵ is hydrogen. In another embodiment, R⁵ is—(CH₂)_(n)OH or hydroxyl. In another embodiment, R⁵ is phenyl. Inanother embodiment, R⁵ is —O—(C₁-C₆)alkyl, optionally substituted withone or more halo. In another embodiment, R⁵ is (C₁-C₆)alkyl, optionallysubstituted with one or more halo.

In one embodiment, R⁶ is hydrogen. In another embodiment, R⁶ is(C₁-C₆)alkyl, optionally substituted with one or more halo.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

Compounds provided herein encompass any of the combinations of R⁴, R⁵,R⁶ and n described above.

In one specific embodiment, R⁴ is methyl. In another embodiment, R⁴ ismethoxy. In another embodiment, R⁴ is —CF₃. In another embodiment, R⁴ isF or Cl.

In another specific embodiment, R⁵ is methyl. In another embodiment, R⁵is —CF₃.

Specific examples include, but are not limited to:

In another embodiment, provided herein are compounds of the formula(III):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R^(d) is:    -   hydrogen;    -   (C₁-C₆)alkyl, optionally substituted with one or more halo;    -   —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionally substituted        with one or more halo;    -   —C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl);    -   —C(O)—(CH₂)_(n)—NR^(e)R^(f), wherein R^(e) and R^(f) are each        independently:        -   hydrogen;        -   (C₁-C₆)alkyl, optionally substituted with one or more halo;            or        -   (C₁-C₆)alkoxy, optionally substituted with one or more halo;            or    -   —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl.-   R⁷ is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo;-   R⁸ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one or    more halo; and-   n is 0, 1, or 2.

In one embodiment, R^(d) is hydrogen. In another embodiment, R^(d) is(C₁-C₆)alkyl, optionally substituted with one or more halo. In anotherembodiment, R^(d) is —C(O)—(C₁-C₈)alkyl. In another embodiment, R^(d) is—C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl). In another embodiment, R^(d) is—C(O)—(CH₂)_(n)—NR^(e)R^(f), wherein R^(e) and R^(f) are as describedherein above. In another embodiment, R^(d) is—C(O)—(CH₂)_(n)—O—(CH₂)_(n)—(C₁-C₆)alkyl.

In one embodiment, R⁷ is hydrogen. In another embodiment, R⁷ is—(CH₂)_(n)OH or hydroxyl. In another embodiment, R⁷ is phenyl. Inanother embodiment, R⁷ is —O—(C₁-C₆)alkyl, optionally substituted withone or more halo. In another embodiment, R⁷ is (C₁-C₆)alkyl, optionallysubstituted with one or more halo.

In one embodiment, R⁸ is hydrogen. In another embodiment, R⁸ is(C₁-C₆)alkyl, optionally substituted with one or more halo.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

Compounds provided herein encompass any of the combinations of R^(d),R⁷, R⁸ and n described above.

In one specific embodiment, R⁷ is methyl. In another embodiment, R^(d)is —C(O)—(C₁-C₆)alkyl. In another embodiment, R^(d) is NH₂. In anotherembodiment, R^(d) is —C(O)—CH₂—O—(C₁-C₆)alkyl.

Specific examples include, but are not limited to:

In another embodiment, In another embodiment, provided herein arecompounds of the formula (IV):

and pharmaceutically acceptable salts, solvates, and stereoisomersthereof, wherein:

-   R^(g) is:    -   —(CH₂)_(n)-(6 to 10 membered aryl);    -   —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or —C(O)—(CH₂)_(n)-(6 to        10 membered heteroaryl), wherein the aryl or heteroaryl is        optionally substituted with one or more of: halo; —SCF₃;        (C₁-C₆)alkyl, itself optionally substituted with one or more        halo; or (C₁-C₆)alkoxy, itself optionally substituted with one        or more halo;    -   —C(O)—(CH₂)_(n)—NHR^(h), wherein R^(h) is:        -   6 to 10 membered aryl, optionally substituted with one or            more of: halo; (C₁-C₆)alkyl, itself optionally substituted            with one or more halo; or (C₁-C₆)alkoxy, itself optionally            substituted with one or more halo; or    -   —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10 membered aryl);-   R⁹ is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or    (C₁-C₆)alkyl, optionally substituted with one or more halo;-   R¹⁰ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted with one    or more halo; and-   n is 0, 1, or 2.

In one embodiment, R^(g) is —(CH₂)_(n)-(6 to 10 membered aryl). Inanother embodiment, R^(g) is —C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or—C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the aryl orheteroaryl is optionally substituted as described above. In anotherembodiment, R^(g) is —C(O)—(CH₂)_(n)—NHR^(h), wherein R^(h) is 6 to 10membered aryl, optionally substituted as described above. In anotherembodiment, R^(g) is —C(O)—(CH₂)_(n)—(CH₂)_(n)-(₆ to 10 membered aryl).

In one embodiment, R⁹ is hydrogen. In another embodiment, R⁹ is—(CH₂)_(n)OH or hydroxyl. In another embodiment, R⁹ is phenyl. Inanother embodiment, R⁹ is —O—(C₁-C₆)alkyl, optionally substituted withone or more halo. In another embodiment, R⁹ is (C₁-C₆)alkyl, optionallysubstituted with one or more halo.

In one embodiment, R¹⁰ is hydrogen. In another embodiment, R¹⁰ is(C₁-C₆)alkyl, optionally substituted with one or more halo.

In one embodiment, n is 0. In another embodiment, n is 1. In anotherembodiment, n is 2.

Compounds provided herein encompass any of the combinations of R^(g),R⁹, R¹⁰ and n described above.

In one specific embodiment, R⁹ is methyl. In another embodiment, R^(g)is —C(O)-phenyl or —C(O)—CH₂-phenyl, wherein the phenyl is optionallysubstituted with methyl, —CF₃, and/or halo. In another embodiment, R^(g)is —C(O)—NH-phenyl, wherein the phenyl is optionally substituted withmethyl, —CF₃, and/or halo.

Specific compounds include, but are not limited to:

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salt” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids. Suitable non-toxic acids include inorganic andorganic acids such as, but not limited to, acetic, alginic, anthranilic,benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic,formic, fumaric, furoic, gluconic, glutamic, glucorenic, galacturonic,glycidic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phenylacetic, propionic, phosphoric, salicylic, stearic, succinic,sulfanilic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Inone embodiment, suitable are hydrochloric, hydrobromic, phosphoric, andsulfuric acids.

As used herein, and unless otherwise specified, the term “solvate” meansa compound that further includes a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Where thesolvent is water, the solvate is a hydrate.

As used herein, and unless otherwise specified, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide thecompound. Examples of prodrugs include, but are not limited to,compounds that comprise biohydrolyzable moieties such as biohydrolyzableamides, biohydrolyzable esters, biohydrolyzable carbamates,biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzablephosphate analogues. Other examples of prodrugs include compounds thatcomprise —NO, —NO₂, —ONO, or —ONO₂ moieties. Prodrugs can typically beprepared using well-known methods, such as those described in Burger'sMedicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E.Wolff ed., 5th ed. 1995), and Design of Prodrugs (H. Bundgaard ed.,Elselvier, New York 1985).

As used herein, and unless otherwise specified, the terms“biohydrolyzable carbamate,” “biohydrolyzable carbonate,”“biohydrolyzable ureide” and “biohydrolyzable phosphate” mean acarbamate, carbonate, ureide and phosphate, respectively, of a compoundthat either: 1) does not interfere with the biological activity of thecompound but can confer upon that compound advantageous properties invivo, such as uptake, duration of action, or onset of action; or 2) isbiologically inactive but is converted in vivo to the biologicallyactive compound. Examples of biohydrolyzable carbamates include, but arenot limited to, carbamates that include lower alkylamine, substitutedethylenediamine, amino acid, hydroxyalkylamine, heterocyclic andheteroaromatic amine, and polyether amine moieties.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/stereomerically pure andenantiomerically/stereomerically enriched compounds provided herein.

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,or greater than about 97% by weight of one stereoisomer of the compoundand less than about 3% by weight of the other stereoisomers of thecompound.

As used herein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, greater than about 70% byweight, or greater than about 80% by weight of one stereoisomer of acompound.

As used herein, and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

As used herein, and unless otherwise indicated, the term “alkyl” refersto a saturated straight chain or branched hydrocarbon having a number ofcarbon atoms as specified herein. Representative saturated straightchain alkyls include -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl,and -n-hexyl; while saturated branched alkyls include -isopropyl,-sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl,3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,2,3-dimethylbutyl, and the like. The term “alkyl” also encompassescycloalkyl.

As used herein, and unless otherwise specified, the term “cycloalkyl”means a specie of alkyl containing from 3 to 15 carbon atoms, withoutalternating or resonating double bonds between carbon atoms. It maycontain from 1 to 4 rings. Examples of unsubstituted cycloalkylsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and adamantyl. A cycloalkyl may be substituted with one ormore of the substituents.

As used herein, the term “aryl” means a carbocyclic aromatic ringcontaining from 5 to 14 ring atoms. The ring atoms of a carbocyclic arylgroup are all carbon atoms. Aryl ring structures include compoundshaving one or more ring structures such as mono-, bi-, or tricycliccompounds as well as benzo-fused carbocyclic moieties such as5,6,7,8-tetrahydronaphthyl and the like. Specifically, the aryl group isa monocyclic ring or bicyclic ring. Representative aryl groups includephenyl, anthracenyl, fluorenyl, indenyl, azulenyl, phenanthrenyl andnaphthyl.

It should be noted that if there is a discrepancy between a depictedstructure and a name given that structure, the depicted structure is tobe accorded more weight. In addition, if the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it.

5.2 Methods of Treatment, Prevention and Management

Provided herein are methods of treating, preventing, and/or managingvarious diseases or disorders using a compound provided herein, or apharmaceutically acceptable salt, solvate (e.g., hydrate), prodrug,clathrate, or stereoisomer thereof. Without being limited by aparticular theory, compounds provided herein can control angiogenesis orinhibit the production of certain cytokines including, but not limitedto, TNF-α, IL-β, IL-12, IL-18, GM-CSF, and/or IL-6. Without beinglimited by a particular theory, compounds provided herein can stimulatethe production of certain other cytokines including IL-10, and also actas a costimulatory signal for T cell activation, resulting in increasedproduction of cytokines such as, but not limited to, IL-12 and/or IFN-γ.In addition, compounds provided herein can enhance the effects of NKcells and antibody-mediated cellular cytotoxicity (ADCC). Further,compounds provided herein may be immunomodulatory and/or cytotoxic, andthus, may be useful as chemotherapeutic agents. Consequently, withoutbeing limited by a particular theory, some or all of suchcharacteristics possessed by the compounds provided herein may renderthem useful in treating, managing, and/or preventing various diseases ordisorders.

Examples of diseases or disorders include, but are not limited to,cancer, disorders associated with angiogenesis, pain including, but notlimited to, Complex Regional Pain Syndrome (“CRPS”), MacularDegeneration (“MD”) and related syndromes, skin diseases, pulmonarydisorders, asbestos-related disorders, parasitic diseases,immunodeficiency disorders, CNS disorders, CNS injury, atherosclerosisand related disorders, dysfunctional sleep and related disorders,hemoglobinopathy and related disorders (e.g., anemia), TNFα relateddisorders, and other various diseases and disorders.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof.

As used herein, and unless otherwise specified, the terms “manage,”“managing” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms thereof. In certain cases, the beneficial effects that asubject derives from a prophylactic or therapeutic agent do not resultin a cure of the disease or disorder.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

Examples of cancer and precancerous conditions include, but are notlimited to, those described in U.S. Pat. Nos. 6,281,230 and 5,635,517 toMuller et al., in various U.S. patent publications to Zeldis, includingpublication nos. 2004/0220144A1, published Nov. 4, 2004 (Treatment ofMyelodysplastic Syndrome); 2004/0029832A1, published Feb. 12, 2004(Treatment of Various Types of Cancer); and 2004/0087546, published May6, 2004 (Treatment of Myeloproliferative Diseases). Examples alsoinclude those described in WO 2004/103274, published Dec. 2, 2004. Allof these references are incorporated herein in their entireties byreference.

Specific examples of cancer include, but are not limited to, cancers ofthe skin, such as melanoma; lymph node; breast; cervix; uterus;gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth;brain; head and neck; throat; testes; kidney; pancreas; bone; spleen;liver; bladder; larynx; nasal passages; and AIDS-related cancers. Thecompounds are also useful for treating cancers of the blood and bonemarrow, such as multiple myeloma and acute and chronic leukemias, forexample, lymphoblastic, myelogenous, lymphocytic, and myelocyticleukemias. The compounds provided herein can be used for treating,preventing or managing either primary or metastatic tumors.

Other specific cancers include, but are not limited to, advancedmalignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma,multiple brain metastase, glioblastoma multiforms, glioblastoma, brainstem glioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasticleukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma,metastatic melanoma (localized melanoma, including, but not limited to,ocular melanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another embodiment, the canceris refractory or resistance to chemotherapy or radiation.

In one embodiment, provided herein are methods of treating, preventingor managing various forms of leukemias such as chronic lymphocyticleukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia,acute myelogenous leukemia and acute myeloblastic leukemia, includingleukemias that are relapsed, refractory or resistant, as disclosed inU.S. publication no. 2006/0030594, published Feb. 9, 2006, which isincorporated in its entirety by reference.

The term “leukemia” refers malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another embodiment, provided herein are methods of treating,preventing or managing various types of lymphomas, includingNon-Hodgkin's lymphoma (NHL). The term “lymphoma” refers a heterogenousgroup of neoplasms arising in the reticuloendothelial and lymphaticsystems. “NHL” refers to malignant monoclonal proliferation of lymphoidcells in sites of the immune system, including lymph nodes, bone marrow,spleen, liver and gastrointestinal tract. Examples of NHL include, butare not limited to, mantle cell lymphoma (MCL), lymphocytic lymphoma ofintermediate differentiation, intermediate lymphocytic lymphoma (ILL),diffuse poorly differentiated lymphocytic lymphoma (PDL), centrocyticlymphoma, diffuse small-cleaved cell lymphoma (DSCCL), follicularlymphoma, and any type of the mantle cell lymphomas that can be seenunder the microscope (nodular, diffuse, blastic and mentle zonelymphoma).

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle). Specific examples of thediseases and disorders associated with, or characterized by, undesiredangiogenesis include, but are not limited to, arthritis, endometriosis,Crohn's disease, heart failure, advanced heart failure, renalimpairment, endotoxemia, toxic shock syndrome, osteoarthritis,retrovirus replication, wasting, meningitis, silica-induced fibrosis,asbestos-induced fibrosis, veterinary disorder, malignancy-associatedhypercalcemia, stroke, circulatory shock, periodontitis, gingivitis,macrocytic anemia, refractory anemia, and 5q-deletion syndrome.

Examples of pain include, but are not limited to those described in U.S.patent publication no. 2005/0203142, published Sep. 15, 2005, which isincorporated herein by reference. Specific types of pain include, butare not limited to, nociceptive pain, neuropathic pain, mixed pain ofnociceptive and neuropathic pain, visceral pain, migraine, headache andpost-operative pain.

Examples of nociceptive pain include, but are not limited to, painassociated with chemical or thermal burns, cuts of the skin, contusionsof the skin, osteoarthritis, rheumatoid arthritis, tendonitis, andmyofascial pain.

Examples of neuropathic pain include, but are not limited to, CRPS typeI, CRPS type II, reflex sympathetic dystrophy (RSD), reflexneurovascular dystrophy, reflex dystrophy, sympathetically maintainedpain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy,shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia,post herpetic neuralgia, cancer related pain, phantom limb pain,fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, centralpost-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain,luetic neuropathy, and other painful neuropathic conditions such asthose induced by drugs such as vincristine and velcade.

As used herein, the terms “complex regional pain syndrome,” “CRPS” and“CRPS and related syndromes” mean a chronic pain disorder characterizedby one or more of the following: pain, whether spontaneous or evoked,including allodynia (painful response to a stimulus that is not usuallypainful) and hyperalgesia (exaggerated response to a stimulus that isusually only mildly painful); pain that is disproportionate to theinciting event (e.g., years of severe pain after an ankle sprain);regional pain that is not limited to a single peripheral nervedistribution; and autonomic dysregulation (e.g., edema, alteration inblood flow and hyperhidrosis) associated with trophic skin changes (hairand nail growth abnormalities and cutaneous ulceration).

Examples of MD and related syndromes include, but are not limited to,those described in U.S. patent publication no. 2004/0091455, publishedMay 13, 2004, which is incorporated herein by reference. Specificexamples include, but are not limited to, atrophic (dry) MD, exudative(wet) MD, age-related maculopathy (ARM), choroidal neovascularisation(CNVM), retinal pigment epithelium detachment (PED), and atrophy ofretinal pigment epithelium (RPE).

Examples of skin diseases include, but are not limited to, thosedescribed in U.S. publication no. 2005/0214328A1, published Sep. 29,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, keratoses and related symptoms, skindiseases or disorders characterized with overgrowths of the epidermis,acne, and wrinkles.

As used herein, the term “keratosis” refers to any lesion on theepidermis marked by the presence of circumscribed overgrowths of thehorny layer, including but not limited to actinic keratosis, seborrheickeratosis, keratoacanthoma, keratosis follicularis (Darier disease),inverted follicular keratosis, palmoplantar keratoderma (PPK, keratosispalmaris et plantaris), keratosis pilaris, and stucco keratosis. Theterm “actinic keratosis” also refers to senile keratosis, keratosissenilis, verruca senilis, plana senilis, solar keratosis, keratoderma orkeratoma. The term “seborrheic keratosis” also refers to seborrheicwart, senile wart, or basal cell papilloma. Keratosis is characterizedby one or more of the following symptoms: rough appearing, scaly,erythematous papules, plaques, spicules or nodules on exposed surfaces(e.g., face, hands, ears, neck, legs and thorax), excrescences ofkeratin referred to as cutaneous horns, hyperkeratosis, telangiectasias,elastosis, pigmented lentigines, acanthosis, parakeratosis,dyskeratoses, papillomatosis, hyperpigmentation of the basal cells,cellular atypia, mitotic figures, abnormal cell-cell adhesion, denseinflammatory infiltrates and small prevalence of squamous cellcarcinomas.

Examples of skin diseases or disorders characterized with overgrowths ofthe epidermis include, but are not limited to, any conditions, diseasesor disorders marked by the presence of overgrowths of the epidermis,including but not limited to, infections associated with papillomavirus, arsenical keratoses, sign of Leser-Trélat, warty dyskeratoma(WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV),ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneousmelanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,confluent and reticulated papillomatosis (CRP), acrochordons, cutaneoushorn, cowden disease (multiple hamartoma syndrome), dermatosis papulosanigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris,molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

Examples of pulmonary disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0239842A1, published Oct. 27,2005, which is incorporated herein by reference. Specific examplesinclude pulmonary hypertension and related disorders. Examples ofpulmonary hypertension and related disorders include, but are notlimited to: primary pulmonary hypertension (PPH); secondary pulmonaryhypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonaryhypertension; pulmonary arterial hypertension (PAH); pulmonary arteryhypertension; idiopathic pulmonary hypertension; thrombotic pulmonaryarteriopathy (TPA); plexogenic pulmonary arteriopathy; functionalclasses I to IV pulmonary hypertension; and pulmonary hypertensionassociated with, related to, or secondary to, left ventriculardysfunction, mitral valvular disease, constrictive pericarditis, aorticstenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonaryvenous drainage, pulmonary venoocclusive disease, collagen vasulardisease, congenital heart disease, HIV virus infection, drugs and toxinssuch as fenfluramines, congenital heart disease, pulmonary venoushypertension, chronic obstructive pulmonary disease, interstitial lungdisease, sleep-disordered breathing, alveolar hypoventilation disorder,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorder, chronic thromboemboli, connective tissue disease, lupusincluding systemic and cutaneous lupus, schistosomiasis, sarcoidosis orpulmonary capillary hemangiomatosis.

Examples of asbestos-related disorders include, but not limited to,those described in U.S. publication no. 2005/0100529, published May 12,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, mesothelioma, asbestosis, malignantpleural effusion, benign exudative effusion, pleural plaques, pleuralcalcification, diffuse pleural thickening, rounded atelectasis, fibroticmasses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, thosedescribed in U.S. publication no. 2006/0154880, published Jul. 13, 2006,which is incorporated herein by reference. Parasitic diseases includediseases and disorders caused by human intracellular parasites such as,but not limited to, P. falcifarium, P. ovale, P. vivax, P. malariae, L.donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. mexicana,L. braziliensis, T. Gondii, B. microti, B. divergens, B. coli, C.parvum, C. cayetanensis, E. histolytica, I. belli, S. mansonii, S.haematobium, Trypanosoma ssp., Toxoplasma ssp., and O. volvulus. Otherdiseases and disorders caused by non-human intracellular parasites suchas, but not limited to, Babesia bovis, Babesia canis, Banesia Gibsoni,Besnoitia darlingi, Cytauxzoon felis, Eimeria ssp., Hammondia ssp., andTheileria ssp., are also encompassed. Specific examples include, but arenot limited to, malaria, babesiosis, trypanosomiasis, leishmaniasis,toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis,cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,filariasis, schistosomiasis, and dermatitis caused by animalschistosomes.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. application Ser. No. 11/289,723, filed Nov. 30,2005. Specific examples include, but not limited to, adenosine deaminasedeficiency, antibody deficiency with normal or elevated Igs,ataxia-tenlangiectasia, bare lymphocyte syndrome, common variableimmunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions, IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective IgG subclass deficiency,transient hypogammaglobulinemia of infancy, Wistcott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0143344, published Jun. 30, 2005,which is incorporated herein by reference. Specific examples include,but are not limited to, include, but are not limited to, AmyotrophicLateral Sclerosis, Alzheimer Disease, Parkinson Disease, Huntington'sDisease, Multiple Sclerosis other neuroimmunological disorders such asTourette Syndrome, delerium, or disturbances in consciousness that occurover a short period of time, and amnestic disorder, or discreet memoryimpairments that occur in the absence of other central nervous systemimpairments.

Examples of CNS injuries and related syndromes include, but are notlimited to, those described in U.S. publication no. 2006/0122228,published Jun. 8, 2006, which is incorporated herein by reference.Specific examples include, but are not limited to, CNS injury/damage andrelated syndromes, include, but are not limited to, primary braininjury, secondary brain injury, traumatic brain injury, focal braininjury, diffuse axonal injury, head injury, concussion, post-concussionsyndrome, cerebral contusion and laceration, subdural hematoma,epidermal hematoma, post-traumatic epilepsy, chronic vegetative state,complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI,central cord syndrome, Brown-Sequard syndrome, anterior cord syndrome,conus medullaris syndrome, cauda equina syndrome, neurogenic shock,spinal shock, altered level of consciousness, headache, nausea, emesis,memory loss, dizziness, diplopia, blurred vision, emotional lability,sleep disturbances, irritability, inability to concentrate, nervousness,behavioral impairment, cognitive deficit, and seizure.

Other disease or disorders include, but not limited to, viral, genetic,allergic, and autoimmune diseases. Specific examples include, but notlimited to, HIV, hepatitis, adult respiratory distress syndrome, boneresorption diseases, chronic pulmonary inflammatory diseases,dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock,hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury,meningitis, psoriasis, fibrotic disease, cachexia, graft versus hostdisease, graft rejection, auto-immune disease, rheumatoid spondylitis,Crohn's disease, ulcerative colitis, inflammatory-bowel disease,multiple sclerosis, systemic lupus erythrematosus, ENL in leprosy,radiation damage, cancer, asthma, or hyperoxic alveolar injury.

Examples of atherosclerosis and related conditions include, but are notlimited to, those disclosed in U.S. publication no. 2002/0054899,published May 9, 2002, which is incorporated herein by reference.Specific examples include, but are not limited to, all forms ofconditions involving atherosclerosis, including restenosis aftervascular intervention such as angioplasty, stenting, atherectomy andgrafting. All forms of vascular intervention are contemplated herein,including diseases of the cardiovascular and renal system, such as, butnot limited to, renal angioplasty, percutaneous coronary intervention(PCI), percutaneous transluminal coronary angioplasty (PTCA), carotidpercutaneous transluminal angioplasty (PTA), coronary by-pass grafting,angioplasty with stent implantation, peripheral percutaneoustransluminal intervention of the iliac, femoral or popliteal arteries,and surgical intervention using impregnated artificial grafts. Thefollowing chart provides a listing of the major systemic arteries thatmay be in need of treatment, all of which are contemplated herein:

Artery Body Areas Supplied Axillary Shoulder and axilla Brachial Upperarm Brachiocephalic Head, neck, and arm Celiac Divides into leftgastric, splenic, and hepatic arteries Common carotid Neck Common iliacDivides into external and internal iliac arteries Coronary Heart Deepfemoral Thigh Digital Fingers Dorsalis pedis Foot External carotid Neckand external head regions External iliac Femoral artery Femoral ThighGastric Stomach Hepatic Liver, gallbladder, pancreas, and duodenumInferior mesenteric Descending colon, rectum, and pelvic wall Internalcarotid Neck and internal head regions Internal iliac Rectum, urinarybladder, external genitalia, buttocks muscles, uterus and vagina Leftgastric Esophagus and stomach Middle sacral Sacrum Ovarian OvariesPalmar arch Hand Peroneal Calf Popliteal Knee Posterior tibial CalfPulmonary Lungs Radial Forearm Renal Kidney Splenic Stomach, pancreas,and spleen Subclavian Shoulder Superior mesenteric Pancreas, smallintestine, ascending and transverse colon Testicular Testes UlnarForearm

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. publication no. 2005/0222209A1,published Oct. 6, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, snoring, sleep apnea,insomnia, narcolepsy, restless leg syndrome, sleep terrors, sleepwalking sleep eating, and dysfunctional sleep associated with chronicneurological or inflammatory conditions. Chronic neurological orinflammatory conditions, include, but are not limited to, ComplexRegional Pain Syndrome, chronic low back pain, musculoskeletal pain,arthritis, radiculopathy, pain associated with cancer, fibromyalgia,chronic fatigue syndrome, visceral pain, bladder pain, chronicpancreatitis, neuropathies (diabetic, post-herpetic, traumatic orinflammatory), and neurodegenerative disorders such as Parkinson'sDisease, Alzheimer's Disease, amyotrophic lateral sclerosis, multiplesclerosis, Huntington's Disease, bradykinesia; muscle rigidity;parkinsonian tremor; parkinsonian gait; motion freezing; depression;defective long-term memory, Rubinstein-Taybi syndrome (RTS); dementia;postural instability; hypokinetic disorders; synuclein disorders;multiple system atrophies; striatonigral degeneration;olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron diseasewith parkinsonian features; Lewy body dementia; Tau pathology disorders;progressive supranuclear palsy; corticobasal degeneration;frontotemporal dementia; amyloid pathology disorders; mild cognitiveimpairment; Alzheimer disease with parkinsonism; Wilson disease;Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3spinocerebellar ataxia; X-linked dystonia parkinsonism; prion disease;hyperkinetic disorders; chorea; ballismus; dystonia tremors; AmyotrophicLateral Sclerosis (ALS); CNS trauma and myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. publication no. 2005/0143420A1,published Jun. 30, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, hemoglobinopathy,sickle cell anemia, and any other disorders related to thedifferentiation of CD34+ cells.

Examples of TNFα related disorders include, but are not limited to,those described in WO 98/03502 and WO 98/54170, both of which areincorporated herein in their entireties by reference. Specific examplesinclude, but are not limited to: endotoxemia or toxic shock syndrome;cachexia; adult respiratory distress syndrome; bone resorption diseasessuch as arthritis; hypercalcemia; Graft versus Host Reaction; cerebralmalaria; inflammation; tumor growth; chronic pulmonary inflammatorydiseases; reperfusion injury; myocardial infarction; stroke; circulatoryshock; rheumatoid arthritis; Crohn's disease; HIV infection and AIDS;other disorders such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, psoriatic arthritis and other arthritic conditions,septic shock, septis, endotoxic shock, graft versus host disease,wasting, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythromatosis, ENL in leprosy, HIV, AIDS, andopportunistic infections in AIDS; disorders such as septic shock,sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, postischemic reperfusion injury, malaria, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic disease,cachexia, graft rejection, oncogenic or cancerous conditions, asthma,autoimmune disease, radiation damages, and hyperoxic alveolar injury;viral infections, such as those caused by the herpes viruses; viralconjunctivitis; or atopic dermatitis.

In other embodiments, the use of compounds provided herein in variousimmunological applications, in particular, as vaccine adjuvants,particularly anticancer vaccine adjuvants, as disclosed in U.S.Provisional Application No. 60/712,823, filed Sep. 1, 2005, which isincorporated herein in its entirety by reference, is also encompassed.These embodiments also relate to the uses of compounds provided hereinin combination with vaccines to treat or prevent cancer or infectiousdiseases, and other various uses of immunomodulatory compounds such asreduction or desensitization of allergic reactions.

Doses of a compound provided herein, or a pharmaceutically acceptablesalt, solvate, clathrate, stereoisomer or prodrug thereof, varydepending on factors such as: specific indication to be treated,prevented, or managed; age and condition of a patient; and amount ofsecond active agent used, if any. Generally, a compound provided herein,or a pharmaceutically acceptable salt, solvate, clathrate, stereoisomeror prodrug thereof, may be used in an amount of from about 0.1 mg toabout 500 mg per day, and can be adjusted in a conventional fashion(e.g., the same amount administered each day of the treatment,prevention or management period), in cycles (e.g., one week on, one weekoff), or in an amount that increases or decreases over the course oftreatment, prevention, or management. In other embodiments, the dose canbe from about 1 mg to about 300 mg, from about 0.1 mg to about 150 mg,from about 1 mg to about 200 mg, from about 10 mg to about 100 mg, fromabout 0.1 mg to about 50 mg, from about 1 mg to about 50 mg, from about10 mg to about 50 mg, from about 20 mg to about 30 mg, or from about 1mg to about 20 mg.

5.3 Second Active Agents

A compound provided herein, or a pharmaceutically acceptable salt,solvate, prodrug, clathrate, or stereoisomer thereof, can be combinedwith other pharmacologically active compounds (“second active agents”)in methods and compositions provided herein. Certain combinations maywork synergistically in the treatment of particular types diseases ordisorders, and conditions and symptoms associated with such diseases ordisorders. A compound provided herein, or a pharmaceutically acceptablesalt, solvate, clathrate, stereoisomer or prodrug thereof, can also workto alleviate adverse effects associated with certain second activeagents, and vice versa.

One or more second active ingredients or agents can be used in themethods and compositions provided herein. Second active agents can belarge molecules (e.g., proteins) or small molecules (e.g., syntheticinorganic, organometallic, or organic molecules).

Examples of large molecule active agents include, but are not limitedto, hematopoietic growth factors, cytokines, and monoclonal andpolyclonal antibodies. Specific examples of the active agents areanti-CD40 monoclonal antibodies (such as, for example, SGN-40); histonedeacetlyase inhibitors (such as, for example, SAHA and LAQ 824);heat-shock protein-90 inhibitors (such as, for example, 17-AAG);insulin-like growth factor-1 receptor kinase inhibitors; vascularendothelial growth factor receptor kinase inhibitors (such as, forexample, PTK787); insulin growth factor receptor inhibitors;lysophosphatidic acid acyltransrerase inhibitors; IkB kinase inhibitors;p38MAPK inhibitors; EGFR inhibitors (such as, for example, gefitinib anderlotinib HCL); HER-2 antibodies (such as, for example, trastuzumab(Herceptin®) and pertuzumab (Omnitarg™)); VEGFR antibodies (such as, forexample, bevacizumab (Avastin™)); VEGFR inhibitors (such as, forexample, flk-1 specific kinase inhibitors, SU5416 and ptk787/zk222584);P13K inhibitors (such as, for example, wortmannin); C-Met inhibitors(such as, for example, PHA-665752); monoclonal antibodies (such as, forexample, rituximab (Rituxan®), tositumomab (Bexxar®), edrecolomab(Panorex®) and G250); and anti-TNF-α antibodies. Examples of smallmolecule active agents include, but are not limited to, anticanceragents and antibiotics (e.g., clarithromycin).

Specific second active compounds that can be combined with compoundsprovided herein vary depending on the specific indication to be treated,prevented or managed.

For instance, for the treatment, prevention or management of cancer,second active agents include, but are not limited to: semaxanib;cyclosporin; etanercept; doxycycline; bortezomib; acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lyticpeptides; maitansine; mannostatin A; marimastat; masoprocol; maspin;matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril;merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, humanchorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wallsk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterialcell wall extract; myriaporone; N-acetyldinaline; N-substitutedbenzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;nitrullyn; oblimersen (Genasense®); O6-benzylguanine; octreotide;okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillylalcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetinA; placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginoneB1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin I; squalamine; stipiamide; stromelysininhibitors; sulfinosine; superactive vasoactive intestinal peptideantagonist; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;zeniplatin; zilascorb; and zinostatin stimalamer.

Specific second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in mutiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

In another embodiment, examples of specific second agents according tothe indications to be treated, prevented, or managed can be found in thefollowing references, all of which are incorporated herein in theirentireties: U.S. Pat. Nos. 6,281,230 and 5,635,517; U.S. publicationnos. 2004/0220144, 2004/0190609, 2004/0087546, 2005/0203142,2004/0091455, 2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880,2006/0122228,and 2005/0143344; and U.S. provisional application No.60/631,870.

Examples of second active agents that may be used for the treatment,prevention and/or management of pain include, but are not limited to,conventional therapeutics used to treat or prevent pain such asantidepressants, anticonvulsants, antihypertensives, anxiolytics,calcium channel blockers, muscle relaxants, non-narcotic analgesics,opioid analgesics, anti-inflammatories, cox-2 inhibitors,immunomodulatory agents, alpha-adrenergic receptor agonists orantagonists, immunosuppressive agents, corticosteroids, hyperbaricoxygen, ketamine, other anesthetic agents, NMDA antagonists, and othertherapeutics found, for example, in the Physician's Desk Reference 2003.Specific examples include, but are not limited to, salicylic acidacetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin(Neurontin®), phenytoin (Dilantin®), carbamazepine (Tegretol®),oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate,hydromorphone, prednisone, griseofulvin, penthonium, alendronate,dyphenhydramide, guanethidine, ketorolac (Acular®), thyrocalcitonin,dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin,reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine,acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®),imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®),fluoxetine (Prozac®), sertraline (Zoloft®), naproxen, nefazodone(Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®), bupropion(Wellbutrin®), mexiletine, nifedipine, propranolol, tramadol,lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan,benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Examples of second active agents that may be used for the treatment,prevention and/or management of macular degeneration and relatedsyndromes include, but are not limited to, a steroid, a lightsensitizer, an integrin, an antioxidant, an interferon, a xanthinederivative, a growth hormone, a neutrotrophic factor, a regulator ofneovascularization, an anti-VEGF antibody, a prostaglandin, anantibiotic, a phytoestrogen, an anti-inflammatory compound or anantiangiogenesis compound, or a combination thereof. Specific examplesinclude, but are not limited to, verteporfin, purlytin, an angiostaticsteroid, rhuFab, interferon-2α, pentoxifylline, tin etiopurpurin,motexafin, lucentis, lutetium,9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione,latanoprost (see U.S. Pat. No. 6,225,348), tetracycline and itsderivatives, rifamycin and its derivatives, macrolides, metronidazole(U.S. Pat. Nos. 6,218,369 and 6,015,803), genistein, genistin, genistin,6′-O-Mal genistin, 6′-O—Ac genistin, daidzein, daidzin, 6′-O-Maldaidzin, 6′-O—Ac daidzin, glycitein, glycitin, 6′-O-Mal glycitin,biochanin A, formononetin (U.S. Pat. No. 6,001,368), triamcinoloneacetomide, dexamethasone (U.S. Pat. No. 5,770,589), thalidomide,glutathione (U.S. Pat. No. 5,632,984), basic fibroblast growth factor(bFGF), transforming growth factor b (TGF-b), brain-derived neurotrophicfactor (BDNF), plasminogen activator factor type 2 (PAI-2), EYE101(Eyetech Pharmaceuticals), LY333531 (Eli Lilly), Miravant, and RETISERTimplant (Bausch & Lomb). All of the references cited herein areincorporated in their entireties by reference.

Examples of second active agents that may be used for the treatment,prevention and/or management of skin diseases include, but are notlimited to, keratolytics, retinoids, α-hydroxy acids, antibiotics,collagen, botulinum toxin, interferon, steroids, and immunomodulatoryagents. Specific examples include, but are not limited to,5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lacticacid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics,collagen, botulinum toxin, interferon, corticosteroid, transretinoicacid and collagens such as human placental collagen, animal placentalcollagen, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm,Zyplast, Resoplast, and Isolagen.

Examples of second active agents that may be used for the treatment,prevention and/or management of pulmonary hypertension and relateddisorders include, but are not limited to, anticoagulants, diuretics,cardiac glycosides, calcium channel blockers, vasodilators, prostacyclinanalogues, endothelin antagonists, phosphodiesterase inhibitors (e.g.,PDE V inhibitors), endopeptidase inhibitors, lipid lowering agents,thromboxane inhibitors, and other therapeutics known to reduce pulmonaryartery pressure. Specific examples include, but are not limited to,warfarin (Coumadin®), a diuretic, a cardiac glycoside, digoxin-oxygen,diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g.,prostaglandin I2 (PGI2), epoprostenol (EPO, Floran®), treprostinil(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine,epoprostenol (Floran®), treprostinil (Remodulin®), prostacyclin,tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat (Vanlev®),irbesartan (Avapro®), pravastatin (Pravachol®), digoxin, L-arginine,iloprost, betaprost, and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment,prevention and/or management of asbestos-related disorders include, butare not limited to, anthracycline, platinum, alkylating agent,oblimersen (Genasense®), cisplatinum, cyclophosphamide, temodar,carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine,carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid,palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenictrioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir,adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa,tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment,prevention and/or management of parasitic diseases include, but are notlimited to, chloroquine, quinine, quinidine, pyrimethamine,sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine,primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin,suramin, pentamidine, melarsoprol, nifurtimox, benznidazole,amphotericin B, pentavalent antimony compounds (e.g., sodiumstiboglucuronate), interfereon gamma, itraconazole, a combination ofdead promastigotes and BCG, leucovorin, corticosteroids, sulfonamide,spiramycin, IgG (serology), trimethoprim, and sulfamethoxazole.

Examples of second active agents that may be used for the treatment,prevention and/or management of immunodeficiency disorders include, butare not limited to: antibiotics (therapeutic or prophylactic) such as,but not limited to, ampicillin, tetracycline, penicillin,cephalosporins, streptomycin, kanamycin, and erythromycin; antiviralssuch as, but not limited to, amantadine, rimantadine, acyclovir, andribavirin; immunoglobulin; plasma; immunologic enhancing drugs such as,but not limited to, levami sole and isoprinosine; biologics such as, butnot limited to, gammaglobulin, transfer factor, interleukins, andinterferons; hormones such as, but not limited to, thymic; and otherimmunologic agents such as, but not limited to, B cell stimulators(e.g., BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growthfactors (e.g., TGF-α), antibodies (e.g., anti-CD40 and IgM),oligonucleotides containing unmethylated CpG motifs, and vaccines (e.g.,viral and tumor peptide vaccines).

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS disorders include, but are notlimited to: opioids; a dopamine agonist or antagonist, such as, but notlimited to, Levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine,tetrabenazine, benzotropine, pargyline, fenodolpam mesylate,cabergoline, pramipexole dihydrochloride, ropinorole, amantadinehydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate,Sinemet CR, and Symmetrel; a MAO inhibitor, such as, but not limited to,iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT inhibitor,such as, but not limited to, tolcapone and entacapone; a cholinesteraseinhibitor, such as, but not limited to, physostigmine saliclate,physostigmine sulfate, physostigmine bromide, meostigmine bromide,neostigmine methylsulfate, ambenonim chloride, edrophonium chloride,tacrine, pralidoxime chloride, obidoxime chloride, trimedoxime bromide,diacetyl monoxim, endrophonium, pyridostigmine, and demecarium; ananti-inflammatory agent, such as, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone or betamethasone and other glucocorticoids; and anantiemetic agent, such as, but not limited to, metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS injuries and related syndromesinclude, but are not limited to, immunomodulatory agents,immunosuppressive agents, antihypertensives, anticonvulsants,fibrinolytic agents, antiplatelet agents, antipsychotics,antidepressants, benzodiazepines, buspirone, amantadine, and other knownor conventional agents used in patients with CNS injury/damage andrelated syndromes. Specific examples include, but are not limited to:steroids (e.g., glucocorticoids, such as, but not limited to,methylprednisolone, dexamethasone and betamethasone); ananti-inflammatory agent, including, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, RHo-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone; a cAMP analog including, but not limited to, db-cAMP; anagent comprising a methylphenidate drug, which comprises1-threo-methylphenidate, d-threo-methylphenidate,d1-threo-methylphenidate, 1-erythro-methylphenidate,d-erythro-methylphenidate, d1-erythro-methylphenidate, and a mixturethereof and a diuretic agent such as, but not limited to, mannitol,furosemide, glycerol, and urea.

Examples of second active agent that may be used for the treatment,prevention and/or management of dysfunctional sleep and relatedsyndromes include, but are not limited to, a tricyclic antidepressantagent, a selective serotonin reuptake inhibitor, an antiepileptic agent(gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam,topiramate), an antiaryhthmic agent, a sodium channel blocking agent, aselective inflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,fenodolpam mesylate, cabergoline, pramipexole dihydrochloride,ropinorole, amantadine hydrochloride, selegiline hydrochloride,carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazid,clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine saliclate, physostigmine sulfate, physostigmine bromide,meostigmine bromide, neostigmine methylsulfate, ambenonim chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxim, endrophonium, pyridostigmine,demecarium, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betamethasone and other glucocorticoids, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of hemoglobinopathy and related disordersinclude, but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrates or butyrate derivatives; nitrousoxide; hydroxy urea; HEMOXIN™ (NIPRISAN™; see U.S. Pat. No. 5,800,819);Gardos channel antagonists such as clotrimazole and triaryl methanederivatives; Deferoxamine; protein C; and transfusions of blood, or of ablood substitute such as Hemospan™ or Hemospan™ PS (Sangart).

Administration of a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, clathrate, stereoisomer or prodrug thereof,and the second active agents to a patient can occur simultaneously orsequentially by the same or different routes of administration. Thesuitability of a particular route of administration employed for aparticular active agent will depend on the active agent itself (e.g.,whether it can be administered orally without decomposing prior toentering the blood stream) and the disease being treated. One ofadministration for compounds provided herein is oral. Routes ofadministration for the second active agents or ingredients are known tothose of ordinary skill in the art. See, e.g., Physicians' DeskReference (60^(th) ed., 2006).

In one embodiment, the second active agent is administered intravenouslyor subcutaneously and once or twice daily in an amount of from about 1to about 1000 mg, from about 5 to about 500 mg, from about 10 to about350 mg, or from about 50 to about 200 mg. The specific amount of thesecond active agent will depend on the specific agent used, the type ofdisease being treated or managed, the severity and stage of disease, andthe amount(s) of compounds provided herein and any optional additionalactive agents concurrently administered to the patient.

As discussed elsewhere herein, also encompassed is a method of reducing,treating and/or preventing adverse or undesired effects associated withconventional therapy including, but not limited to, surgery,chemotherapy, radiation therapy, hormonal therapy, biological therapyand immunotherapy. Compounds provided herein and other activeingredients can be administered to a patient prior to, during, or afterthe occurrence of the adverse effect associated with conventionaltherapy.

5.4 Cycling Therapy

In certain embodiments, the prophylactic or therapeutic agents providedherein are cyclically administered to a patient. Cycling therapyinvolves the administration of an active agent for a period of time,followed by a rest (i.e., discontinuation of the administration) for aperiod of time, and repeating this sequential administration. Cyclingtherapy can reduce the development of resistance to one or more of thetherapies, avoid or reduce the side effects of one of the therapies,and/or improve the efficacy of the treatment.

Consequently, in one embodiment, a compound provided herein isadministered daily in a single or divided doses in a four to six weekcycle with a rest period of about a week or two weeks. Cycling therapyfurther allows the frequency, number, and length of dosing cycles to beincreased. Thus, another embodiment encompasses the administration of acompound provided herein for more cycles than are typical when it isadministered alone. In yet another embodiment, a compound providedherein is administered for a greater number of cycles than wouldtypically cause dose-limiting toxicity in a patient to whom a secondactive ingredient is not also being administered.

In one embodiment, a compound provided herein is administered daily andcontinuously for three or four weeks at a dose of from about 0.1 mg toabout 500 mg per day, followed by a rest of one or two weeks. In otherembodiments, the dose can be from about 1 mg to about 300 mg, from about0.1 mg to about 150 mg, from about 1 mg to about 200 mg, from about 10mg to about 100 mg, from about 0.1 mg to about 50 mg, from about 1 mg toabout 50 mg, from about 10 mg to about 50 mg, from about 20 mg to about30 mg, or from about 1 mg to about 20 mg, followed by a rest.

In one embodiment, a compound provided herein and a second activeingredient are administered orally, with administration of the compoundprovided herein occurring 30 to 60 minutes prior to the second activeingredient, during a cycle of four to six weeks. In another embodiment,the combination of a compound provided herein and a second activeingredient is administered by intravenous infusion over about 90 minutesevery cycle.

Typically, the number of cycles during which the combination treatmentis administered to a patient will be from about one to about 24 cycles,from about two to about 16 cycles, or from about four to about threecycles.

5.5 Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt, solvate, stereoisomer, clathrate, orprodrug thereof. Pharmaceutical compositions and dosage forms canfurther comprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are disclosed in Section 4.3,above.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or di-saccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg. Inother embodiments, dosage forms comprise a compound provided herein inan amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50,100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise the second active ingredientin an amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound provided herein, and any optionaladditional active agents concurrently administered to the patient.

5.5.1 Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or nonaqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. In oneembodiment, pharmaceutical compositions comprise from about 0.5 to about15 weight percent of disintegrant, or from about 1 to about 5 weightpercent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, anhydrous lactose, microcrystalline cellulose,polyvinylpyrrolidone, stearic acid, colloidal anhydrous silica, andgelatin.

5.5.2 Controlled Release Dosage Forms

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. In one embodiment, provided aresingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled-release.

In one embodiment, controlled-release pharmaceutical products improvedrug therapy over that achieved by their non-controlled counterparts. Inanother embodiment, the use of a controlled-release preparation inmedical treatment is characterized by a minimum of drug substance beingemployed to cure or control the condition in a minimum amount of time.Advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

In another embodiment, the controlled-release formulations are designedto initially release an amount of drug (active ingredient) that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release of other amounts of drug to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In one embodiment, in order to maintain a constant level of drug in thebody, the drug can be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

5.5.3 Parental Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

5.5.4 Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's Pharmaceutical Sciences, 16thand 18th eds., Mack Publishing, Easton Pa. (1980 & 1990); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980 & 1990).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

5.6 Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise additional active ingredients such asoblimersen (Genasense®), melphalan, G-CSF, GM-CSF, EPO, topotecan,dacarbazine, irinotecan, taxotere, IFN, COX-2 inhibitor, pentoxifylline,ciprofloxacin, dexamethasone, IL2, IL8, IL18, Ara-C, vinorelbine,isotretinoin, 13 cis-retinoic acid, or a pharmacologically active mutantor derivative thereof, or a combination thereof. Examples of theadditional active ingredients include, but are not limited to, thosedisclosed herein (see, e.g., section 4.3).

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

6. EXAMPLES

Certain embodiments of the invention are illustrated by the followingnon-limiting examples.

6.1 3-(5-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-amino-6-methylbenzoic acid (10.75 g, 71.1 mmol)and CDI (10.75 g, 66.3 mmol) in acetonitrile (150 mL) was stirred atroom temperature for 1 hour. To the suspension, was added3-amino-piperidine-2,6-dione hydrogen chloride (10.75 g, 65.3 mmol) andsodium hydrogen carbonate (8.0 g, 95 mmol), and the mixture was heatedat 50° C. for 18 hours. The suspension was cooled to room temperature,filtered, and washed with acetonitrile (50 mL), water (2×50 mL),methanol (50 mL), and ethyl acetate (50 mL) to give2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide as a white solid(9.89 g, 58% yield): ¹H NMR (DMSO-d₆) δ 1.98-2.17 (m, 5H, CH₂, CH₃)2.51-2.56 (m, 1H, CHH), 2.74-2.86 (m, 1H, CHH), 4.68-4.77 (m, 1H, NCH),5.18 (s, 2H, NH₂), 6.38 (d, J=7 Hz, 1H, Ar), 6.50 (d, J=7 Hz, 1H, Ar),6.94 (t; J=7 Hz, 1H, Ar), 8.59 (d, J=8 Hz, 1H, NH), 10.90 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 19.14, 23.75, 30.99, 49.10, 112.37, 17.21, 122.28,128.96, 134.61, 145.22, 168.36, 172.84, 173.00; LCMS: MH=262.

Step 2: A solution of2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (0.60 g, 2.2mmol), trimethyl orthoformate (3 mL, 26.8 mmol), and p-toluene sulfonicacid (0.060 g) in acetonitrile (20 mL) was heated to reflux for 30hours. The mixture was cooled to room temperature. To the mixture, water(75 mL) and ether (20 mL) were added, and the resulting mixture wasstirred for 2 hours. The suspension was filtered and washed with waterand ether (50 mL each) to give3-(5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a whitesolid (0.28 g, 47% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm,1 mL/min, 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 3.08 min (99%); mp: 262-264°C.; ¹H NMR (DMSO-d₆) δ 2.09-2.16 (m, 1H, CHH), 2.62-2.84 (m, 6H, CH₂,CH₃, CHH), 5.42 (brs, 1H, NCH), 7.32 (d, J=7 Hz, 1H, Ar), 7.52 (d, J=8Hz, 1H, Ar), 7.69 (t, J=8 Hz, 1H, Ar), 8.30 (s, 1H, CH), 11.12 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 22.35, 22.62, 30.88, 58.00, 119.81, 125.36,129.57, 133.72, 140.15, 147.08, 149.07, 160.21, 169.91, 172.33, 172.44;LCMS: MH=272; Anal. Calcd. for C₁₄H₁₃N₃O₃: C, 61.99; H, 4.83; N, 15.49.Found: C, 61.67; H, 4.40; N, 15.41.

6.2 3-(2,5-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide(1.00 g, 3.8 mmol) and triethyl orthoacetate (0.9 mL, 4.9 mmol) in DMF(10 mL) was heated to reflux for 1 hour. The mixture was cooled to roomtemperature. To the solution, Celite (40 mL) was added, and the solventwas removed in vacuo. The solid was loaded on a SIM and purified withISCO flash gel chromatography (silica gel, CH₃OH/CH₂Cl₂) to give3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as anoff-white solid (0.46 g, 43% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 2.95 min (96%);mp: 292-294° C.; ¹H NMR (DMSO-d₆) δ 2.11-2.18 (m, 1H, CHH), 2.55-2.65(m, 2H, CH₂), 2.60 (s, 3H, CH₃), 2.69 (s, 3H, CH₃), 2.78-2.85 (m, 1H,CHH), 5.19 (dd, J=6, 11 Hz, 1H, NCH), 7.25 (d, J=8 Hz, 1H, Ar), 7.43 (d,J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.99 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.82, 22.43, 23.32, 30.55, 56.33, 118.69, 124.73, 128.82,133.72, 139.82, 148.34, 154.58, 161.03, 169.61, 172.60; LCMS: MH=286;Anal. Calcd. for C₁₅H₁₅N₃O₃+1 H₂O: C, 59.26; H, 5.68; N, 13.66. Found:C, 59.26; H, 5.68; N, 13.66.

6.3 3S-3-(2,5-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A stirred suspension of 2,5-dimethyl-benzo[d][1,3]oxazin-4-one(7.4 g, 42 mmol), 4S-4-amino-4-carbamoyl-butyric acid tert-butyl ester(H-Glu(OtBu)-NH2) (10.0 g, 42 mmol), imidazole (6.3 g, 92 mmol) andtriphenyl phosphite (13.2 mL, 50 mmol) in acetonitrile (100 mL) washeated to reflux for 21 hours. The mixture was allowed to cool to 30° C.To the mixture, was added water (100 mL) and hexane (100 mL) to givethree layers. The lower two layers were separated and extracted withmethylene chloride (2×100 mL). All three organic layers were combined.To the solution, was added Celite (2 teaspoons). The solvent was removedin vacuo. The solid was placed in a SIM and purified by ISCO columnchromatography (Silica gel, CH₃CN/CH₂Cl₂, 0% gradient to 50% in 20 min)to give 4S-4-carbamoyl-4-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-butyricacid tert-butyl ester as a white solid (12.9 g, 86% yield). The productwas used in the next step without further purification.

Step 2: A suspension of4S-4-carbamoyl-4-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-butyric acidtert-butyl ester (8.7 g, 24 mmol) and HCl in ether (60 mL, 2N, 120 mmol)was stirred at room temperature for 2 days. The solvent was removed invacuo. The solid was stirred with ether (50 mL) for 1 hour. Thesuspension was filtered and washed with ether (20 mL) to give a yellowsolid. The solid was stirred in methanol (50 mL) overnight. Thesuspension was filtered and washed with methanol to give4S-4-carbamoyl-4-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-butyric acid asa white solid (7.0 g, 96% yield). The product was used in the next stepwithout further purification.

Step 3: To a stirred suspension of4S-4-carbamoyl-4-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-butyric acid(7.2 g, 24 mmol) in methylene chloride (250 mL), was added thionylchloride (7 mL, 96 mmol) using a syringe pump (2 mL/min) at −40° C.After 10 minutes, pyridine (7.7 mL, 96 mmol) was added to the mixtureusing a syringe pump (2 mL/min). The mixture was stirred at −40° C. for5 hours. To the mixture, was added water (20 mL). After 5 minutes,sodium hydrogen carbonate (sat 100 mL) was added to the mixture. After10 minutes, the mixture was transferred to a 0° C. bath and kept for 30minutes. The organic layer was separated and concentrated in vacuo togive a white solid. The solid was mixed with the first aqueous layer,and the suspension was stirred for 10 minutes. The suspension wasfiltered and washed with water (50 mL), sodium hydrogen carbonate (sat50 mL), and water (2×50 mL) to give an off-white solid. The solid wasdissolved in acetonitrile (150 mL), and Celite (3 teaspoons) was added.The solvent was removed in vacuo. The solid was distributed in threeSIMs, and each SIM was purified by ISCO column chromatography (Silicagel, CH₃CN/CH₂Cl₂, 0% gradient to 50% in 15 min) to give3S-3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (2.92 g, 43% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 4.50 min (99.8%);Chiral HPLC: ChiralPak AD 1 mL/min, 240 nm, 50/50 iPrOH/hexane, 12.62(99.93%) (S-isomer), 18.58 (0.07%) (R-isoemer) 99.86% ee; mp: 241-243°C.; ¹N NMR (DMSO-d₆) δ 2.11-2.18 (m, 1H, CHH), 2.55-2.65 (m, 2H, CH₂),2.60 (s, 3H, CH₃), 2.69 (s, 3H, CH₃), 2.78-2.85 (m, 1H, CHH), 5.19 (dd,J=6, 11 Hz, 1H, NCH), 7.25 (d, J=8 Hz, 1H, Ar), 7.43 (d, J=8 Hz, 1H,Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.99 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.82, 22.43, 23.32, 30.55, 56.33, 118.69, 124.73, 128.82, 133.72,139.82, 148.34, 154.58, 161.03, 169.61, 172.60; LCMS: MH=286; Anal Calcdfor C₁₅H₁₅N₃O₃+0.5 H₂O: C, 61.22; H, 5.48; N, 14.28; H₂O, 3.06. Found:C, 60.98; H, 5.54; N, 14.21; H₂O, 2.89.

6.4 3R-3-(2,5-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A stirred suspension of 2,5-dimethyl-benzo[d][1,3]oxazin-4-one(7.8 g, 45 mmol), 2R-2-amino-4-carbamoyl-butyric acid tert-butyl ester(9 g, 45 mmol), imidazole (3.6 g, 53 mmol) and triphenyl phosphite (17mL, 65 mmol) in acetonitrile (100 mL) was heated to reflux for 21 hours.The mixture was allowed to cool to 30° C. To the mixture, was addedwater (100 mL) and methylene chloride (200 mL). The aqueous layer wasextracted with methylene chloride (200 mL). The combined organic layerswas washed with sodium hydrogen carbonate (sat 100 mL). To the organiclayer, was added Celite (2 teaspoons). The solvent was removed in vacuo.The solid was distributed in three SIMs, and each SIM was purified byISCO column chromatography (Silica gel, CH₃CN/CH₂Cl₂, 0% gradient to 50%in 20 min) to give4R-4-carbamoyl-2-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-butyric acidtert-butyl ester as a white solid (3.4 g, 21% yield). The product wasused in the next step without further purification.

Step 2: A suspension of4R-4-carbamoyl-4-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-butyric acidtert-butyl ester (3.4 g, 9.4 mmol) and HCl in ether (50 mL, 2N, 100mmol) was stirred at room temperature for 4 days. The solvent wasremoved in vacuo. To the solid, was added methanol (30 mL). The solventwas removed in vacuo again. The solid was stirred in methylene chloride(30 mL) overnight. The suspension was filtered and washed with methylenechloride (20 mL) to give4R-4-carbamoyl-2-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-butyric acid asa yellow solid (2.6 g, 91% yield). The product was used in the next stepwithout further purification.

Step 3: To a stirred suspension of4R-4-carbamoyl-2-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-butyric acid(3.2 g, 11 mmol) in methylene chloride (130 mL), was added thionylchloride (3.1 mL, 43 mmol) using a syringe pump (2 mL/min) at −40° C.After 10 minutes, pyridine (3.5 mL, 43 mmol) was added using a syringepump (2 mL/min). The mixture was stirred at −40° C. for 4 hours. To themixture, was added water (20 mL). After 5 minutes, sodium hydrogencarbonate (sat 140 mL) was added to the mixture. After 10 minutes, themixture was transferred to a 0° C. bath and kept for 30 minutes. Theorganic solvent was removed in vacuo. The suspension was filtered andwashed with water (50 mL) to give an off-white solid. The solid wasdissolved in methanol (150 mL), and Celite (2 teaspoons) was added. Thesolvent was removed in vacuo. The solid was distributed in two SIMs, andeach SIM was purified by ISCO column chromatography (Silica gel,CH₃CN/CH₂Cl₂, 0% gradient to 50% in 15 min) to give3R-3-(2,5-dimethyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (1.4 g, 46% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 2.75 min (99.3%); ChiralHPLC: ChiralPak AD 1 mL/min, 240 nm, 50/50 iPrOH/hexane, 6.23 (4.22%)(S-isomer), 8.23 (95.38%) (R-isoemer), 91.53% ee; mp: 280° C. (decomp);¹H NMR (DMSO-d₆) δ 2.11-2.18 (m, 1H, CHH), 2.55-2.65 (m, 2H, CH₂), 2.60(s, 3H, CH₃), 2.69 (s, 3H, CH₃), 2.78-2.85 (m, 1H, CHH), 5.19 (dd, J=6,11 Hz, 1H, NCH), 7.25 (d, J=8 Hz, 1H, Ar), 7.43 (d, J=8 Hz, 1H, Ar),7.64 (t, J=8 Hz, 1H, Ar), 10.99 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.82,22.43, 23.32, 30.55, 56.33, 118.69, 124.73, 128.82, 133.72, 139.82,148.34, 154.58, 161.03, 169.61, 172.60; LCMS: MH=286; Anal Calcd forC₁₅H₁₅N₃O₃+0.35 H₂O: C, 61.78; H, 5.43; N, 14.41; H₂O, 2.16. Found: C,61.82; H, 5.08; N, 14.32; H₂O, 2.17.

6.5 3-(2-HYDROXY-5-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide(1.00 g, 3.8 mmol), CDI (0.62 g, 3.8 mmol) and DMAP (0.10 g, 0.82 mmol)in acetonitrile (12 mL) was heated at 150° C. in a microwave oven for 10minutes. The suspension was filtered and washed with acetonitrile (2×20mL), water (2×20 mL), HCl (1N, 25 mL), water (25 mL), methanol (2×20mL), and ethyl acetate (2×20 mL) to give3-(2-hydroxy-5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione asan off-white solid (0.89 g, 81% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 5.72 min (99%);mp: 373-375° C.; ¹H NMR (DMSO-d₆) δ 1.90-1.97 (m, 1H, CHH), 2.49-2.58(m, 2H, CH₂), 2.61 (s, 1.5H, CH₃), 2.69 (s, 1.5H, CH₃), 2.81-2.92 (m,1H, CHH), 5.55 (dd, J=5, 11 Hz, 0.5H, NCH), 5.72 (dd, J=5, 11 Hz, 0.5H,NCH), 6.99-7.08 (m, 2H, Ar), 7.50-7.55 (m, 1H, Ar), 10.92 (s, 0.5H, OH),11.42 (s, 0.5H, NH), 11.56 (s, 0.5H, NH) (observed at 350K); ¹³C NMR(DMSO-d₆) δ 20.90, 21.38, 22.11, 22.41, 30.72, 30.77, 49.74, 50.99,111.52, 112.15, 113.38, 125.67, 134.26, 134.34, 140.29, 140.63, 141.09,141.45, 148.77, 149.99, 161.60, 162.39, 170.00, 170.38, 172.74; LCMS:MH=288; Anal. Calcd. for C₁₄H₁₃N₃O₄: C, 58.53; H, 4.56; N, 14.63. Found:C, 58.40; H, 4.32; N, 14.59.

6.63S-3-(2,5-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-3-METHYL-PIPERIDINE-2,6-DIONE

A stirred suspension of 2,5-dimethyl-benzo[d][1,3]oxazin-4-one (1.4 g,8.1 mmol), 3S-3-amino-3-methyl-piperidine-2,6-dione hydrogen bromide(1.8 g, 8.1 mmol), imidazole (1.2 g, 18 mmol) and triphenyl phosphite(2.6 mL, 9.7 mmol) in acetonitrile (50 mL) was heated in a 65° C. oilbath overnight. The mixture was allowed to cool to room temperature. Tothe mixture, was added Celite. The solvent was removed in vacuo. Thesolid was placed in a SIM and purified by ISCO column chromatography(Silica gel, CH₃CN/CH₂Cl₂ 0% gradient to 100% in 15 min) to give3S-3-(2,5-Dimethyl-4-oxo-4H-quinazolin-3-yl)-3-methyl-piperidine-2,6-dioneas a white solid (220 mg, 9% yield). HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 3.43 min (99.4%);mp: 187-189° C. (decomp); ¹H NMR (DMSO-d₆) δ 1.90 (s, 3H, CH₃),2.36-2.42 (m, 1H, CHH), 2.49-2.85 (m, 9H, 2CH₃, 3CHH), 7.22 (d, J=7 Hz,1H, Ar), 7.37 (d, J=8 Hz, 1H, Ar), 7.62 (t, J=8 Hz, 1H, Ar), 10.79 (s,1H, NH); ¹³C NMR (DMSO-d₆) δ 22.17, 24.42, 26.21, 28.13, 28.95, 62.59,118.82, 123.96, 128.59, 133.64, 139.48, 147.44, 153.73, 163.77, 171.45,173.10; LCMS: MH=300; Anal Calcd for C₁₆H₁₇N₃O₃: C, 64.20; H, 5.72; N,14.04. Found: C, 64.08; H, 5.58; N, 13.86.

6.73R-3-(2,5-DIMETHYL-4-OXO-4H-QUINAZOLIN-3-YL)-3-METHYL-PIPERIDINE-2,6-DIONE

A stirred suspension of 2,5-dimethyl-benzo[d][1,3]oxazin-4-one (1.6 g,9.0 mmol), 3R-3-amino-3-methyl-piperidine-2,6-dione hydrogen bromide(2.0 g, 9.0 mmol), imidazole (1.3 g, 20 mmol) and triphenyl phosphite(2.4 mL, 9.0 mmol) in acetonitrile (50 mL) was heated in a 65° C. oilbath overnight. The mixture was allowed to cool to room temperature. Tothe mixture, was added Celite. The solvent was removed in vacuo. Thesolid was placed in a SIM and purified by ISCO column chromatography(Silica gel, CH₃CN/CH₂Cl₂ 0% gradient to 100% in 15 min) to give3R-3-(2,5-Dimethyl-4-oxo-4H-quinazolin-3-yl)-3-methyl-piperidine-2,6-dioneas a white solid (90 mg, 3.4% yield). HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 6.46 min (99.4%);mp: 298-301° C.; ¹H NMR (DMSO-d₆) δ 1.90 (s, 3H, CH₃), 2.36-2.42 (m, 1H,CHH), 2.49-2.85 (m, 9H, 2CH₃, 3CHH), 7.22 (d, J=7 Hz, 1H, Ar), 7.37 (d,J=8 Hz, 1H, Ar), 7.62 (t, J=8 Hz, 1H, Ar), 10.79 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 22.17, 24.42, 26.21, 28.13, 28.95, 62.59, 118.82, 123.96,128.59, 133.64, 139.48, 147.44, 153.73, 163.77, 171.45, 173.10; LCMS:MH=300; Anal Calcd for C₁₆H₁₇N₃O₃: C, 64.20; H, 5.72; N, 14.04. Found:C, 63.81; H, 5.69; N, 13.92.

6.8 3-(5-METHOXY-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-6-methoxybenzoic acid (2.0 g, 12 mmol)and imidazole (1.0 g, 14 mmol) in acetonitrile (20 mL), was added acetylchloride (1.0 mL, 14 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.0 g, 12 mmol),imidazole (1.8 g, 26 mmol) and triphenyl phosphite (3.8 mL, 14 mmol) andheated to reflux for 22 hours. To the mixture, was added water (60 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50mL) to give3-(5-methoxy-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione asa white solid (1.3 g, 35% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 15/85 CH₃CN/0.1% H₃PO₄, 3.37 min (99.4%);mp: 274-276° C.; ¹H NMR (DMSO-d₆) δ 2.09-2.16 (m, 1H, CHH), 2.51-2.63(m, 5H, CH₃, 2CHH), 2.72-2.89 (m, 1H, CHH), 3.83 (s, 3H, CH₃), 5.14 (dd,J=6, 11 Hz, 1H, NCH), 6.98 (d, J=8 Hz, 1H, Ar), 7.12 (d, J=8 Hz, 1H,Ar), 7.69 (t, J=8 Hz, 1H, Ar), 10.96 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.84, 23.36, 30.55, 55.85, 56.16, 107.96, 109.91, 118.26, 134.98,149.24, 155.30, 158.13, 159.42, 169.63, 172.63; LCMS: MH=302; Anal Calcdfor C₁₅H₁₅N₃O₄+1.6 H₂O: C, 54.57; H, 5.56; N, 12.73. Found: C, 54.19; H,5.42; N, 12.55.

6.9 3-(5-FLUORO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-6-fluorobenzoic acid (5.3 g, 34 mmol)and imidazole (2.8 g, 41 mmol) in acetonitrile (60 mL), was added acetylchloride (2.9 mL, 41 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (6.1 g, 37 mmol),imidazole (5.1 g, 75 mmol) and triphenyl phosphite (10.6 mL, 41 mmol)and heated to reflux for 22 hours. To the mixture, was added water (60mL). The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give a white solid, which wasstirred in methanol (50 mL) overnight. The suspension was washed withmethanol (30 mL) and water (30 mL) to give3-(5-fluoro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (7.6 g, 78% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 3.8 min (99.6%); mp:275-277° C.; ¹H NMR (DMSO-d₆) δ 2.13-2.20 (m, 1H, CHH), 2.57-2.69 (m,5H, CH₃, 2CHH), 2.77-2.90 (m, 1H, CHH), 5.25 (dd, J=6, 11 Hz, 1H, NCH),7.26 (ddd, J=0.6, 8, 11 Hz, 1H, Ar), 7.44 (d, J=8 Hz, 1H, Ar), 7.80 (dt,J=5, 8 Hz 1H, Ar), 11.04 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.73, 23.45,30.57, 56.45, 109.79 (d, J_(C—F)=6 Hz), 112.89 (d, J_(C-F)=21 Hz),122.64 (d, J_(C-F)=4 Hz), 135.39 (d, J_(C-F)=11 Hz), 148.86, 156.22,157.46, 160.15 (d, J_(C-F)=264 Hz), 169.38, 172.57; LCMS: MH=290; AnalCalcd for C₁₄H₁₂N₃O₃F: C, 58.13; H, 4.18; N, 14.53; F, 6.57. Found: C,57.98; H, 4.00; N, 14.45; F, 6.73.

6.10 3-(5-CHLORO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-6-chlorobenzoic acid (2.3 g, 13 mmol)and imidazole (1.1 g, 16 mmol) in acetonitrile (25 mL), was added acetylchloride (1.1 mL, 16 mmol) at room temperature. The mixture was stirredat room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.2 g, 13 mmol),imidazole (2.0 g, 30 mmol) and triphenyl phosphite (4.2 mL, 16 mmol) andheated to reflux for 22 hours. To the mixture, was added water (60 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), and water (50 mL) to give a white solid, which waspurified with preparative HPLC (C18 20/80 CH₃CN/H₂O) to give3-(5-chloro-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (1.3 g, 31% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 25/75 CH₃CN/0.1% H₃PO₄, 4.16 min (99.9%); mp: 315°C. (decomp); ¹H NMR (DMSO-d₆) δ 2.13-2.19 (m, 1H, CHH), 2.57-2.68 (m,5H, CH₃, 2CHH), 2.78-2.85 (m, 1H, CHH), 5.23 (dd, J=5, 11 Hz, 1H, NCH),7.51-7.58 (m, 2H, Ar), 7.74 (t, J=8 Hz, 1H, Ar), 11.03 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 20.63, 23.48, 30.53, 56.61, 117.14, 126.18, 128.98,132.24, 134.52, 149.27, 155.99, 158.39, 169.38, 172.56; LCMS: MH=306,308; Anal Calcd for C₁₄H₁₂N₃O₃Cl+1 H₂O: C, 51.94; H, 4.36; N, 12.98; Cl,10.95. Found: C, 51.91; H, 4.24; N, 12.93; Cl, 10.20.

6.113-(2-METHYL-4-OXO-5-TRIFLUOROMETHYL-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred mixture of 2-amino-6-(trifluoromethyl)benzoic acid (3.0 g,15 mmol) and imidazole (1.2 g, 18 mmol) in acetonitrile (30 mL), wasadded acetyl chloride (1.3 mL, 18 mmol) at room temperature. The mixturewas stirred at room temperature overnight. To the mixture, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.4 g, 15 mmol),imidazole (2.2 g, 32 mmol) and triphenyl phosphite (4.6 mL, 18 mmol) andheated to reflux for 22 hours. To the mixture, was added water (100 mL).The suspension was filtered and washed with water (2×50 mL), ethylacetate (2×50 mL), sodium hydrogen carbonate (sat, 50 mL) and water (50mL) to give3-(2-methyl-4-oxo-5-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-dioneas a white solid (2.02 g, 51% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 4.84 min (99.9%);mp: 268-270° C.; ¹H NMR (DMSO-d₆) δ 2.14-2.22 (m, 1H, CHH), 2.55-2.70(m, 5H, CH₃, 2CHH), 2.76-2.92 (m, 1H, CHH), 5.29 (dd, J=6, 11 Hz, 1H,NCH), 7.89-7.98 (m, 3H, Ar), 11.06 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ20.45, 23.27, 30.43, 56.74, 117.19, 123.19 (q, J_(C-F)=273 Hz), 125.75(q, J_(C-F)=7 Hz), 126.42 (q, J_(C-F)=32 Hz), 132.05, 133.97, 149.12,156.58, 157.59, 169.19, 172.48; LCMS: MH=340; Anal Calcd forC₁₅H₁₂N₃O₃F₃+1 H₂O: C, 50.43; H, 3.95; N, 11.76; F, 15.95. Found: C,50.26; H, 3.82; N, 11.66; F, 15.71.

6.12 3-(5-CHLORO-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-amino-6-chlorobenzoic acid (3.0 g, 17 mmol) andCDI (2.6 g, 16 mmol) in acetonitrile (40 mL) was stirred at roomtemperature for 1.5 hours. To the suspension, was added3-amino-piperidine-2,6-dione hydrogen chloride (2.6 g, 16 mmol) andsodium hydrogen carbonate (1.8 g, 21 mmol), and the mixture was heatedat 50° C. for 21 hours. The suspension was cooled to room temperaturefor 1 hour. The suspension was filtered and washed with water (50 mL)and ethyl acetate (20 mL). The solid was dried in a vacuum ovenovernight to give2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-chloro-benzamide as a white solid(1.7 g, 35% yield): HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1mL/min, 240 nm, 5/95 grad to 95/5 for 5 min CH₃CN/0.1% H₃PO₄, 4.01; ¹HNMR (DMSO-d₆) δ 1.92-1.98 (m, 1H, CHH), 2.05-2.20 (m, 1H, CHH),2.49-2.57 (m, 1H, CHH), 2.76-2.88 (m, 1H, CHH), 4.67-4.76 (m, 1H, NCH),5.61 (s, 2H, NH₂), 6.57 (d, J=8 Hz, 1H, Ar), 6.63 (d, J=8 Hz, 1H, Ar),7.04 (t; J=8 Hz, 1H, Ar), 8.83 (d, J=8 Hz, 1H, NH), 10.95 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 23.50, 30.96, 49.31, 113.29, 115.51, 120.97, 130.03,130.19, 147.03, 165.60, 172.92, 172.97; LCMS: MH=282, 284.

Step 2: A solution of2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-chloro-benzamide (0.8 g, 2.8mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (280mg) was heated to 150° C. via a microwave oven for 30 minutes. To themixture, was added methanol (15 mL), and the mixture was stirred for 5minutes. The suspension was filtered and washed with methanol to give3-(5-chloro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a whitesolid (400 mg, 48% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm,1 mL/min, 240 nm, 30/70 CH₃CN/0.1% H₃PO₄, 2.35 min (99.2%); mp: 308-310°C.; ¹H NMR (DMSO-d₆) δ 2.13-2.19 (m, 1H, CHH), 2.57-2.72 (m, 2H, 2CHH),2.83-2.89 (m, 1H, CHH), 5.43 (br, 1H, NCH), 7.60 (dd, J=1, 8 Hz, 1H,Ar), 7.66 (dd, J=1, 8 Hz, 1H, Ar), 7.79 (t, J=8 Hz, 1H, Ar), 8.39 (s,1H, CH), 11.16 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 22.18, 30.84, 56.16,118.35, 126.81, 129.74, 132.45, 134.54, 148.18, 149.98, 157.62, 169.68,172.39; LCMS: MH=292, 294; Anal Calcd for C₁₃H₁₀N₃O₃Cl+0.15 H₂O: C,53.04; H, 3.53; N, 14.27. Found: C, 52.68; H, 3.14; N, 14.17.

6.13 3-(2-ETHYL-5-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-amino-6-methylbenzoic acid (45 g, 297 mmol) andCDI (45 g, 278 mmol) in acetonitrile (500 mL) was stirred at roomtemperature for 1.5 hours. To the suspension, was added3-amino-piperidine-2,6-dione hydrogen chloride (45 g, 273 mmol) andsodium hydrogen carbonate (34 g, 409 mmol), and the mixture was heatedat 50° C. for 21 hours. The suspension was cooled to room temperaturefor 1 hour. The suspension was filtered. The solid was stirred withwater (150 mL) and ethyl acetate (150 mL) for 3 hours. The suspensionwas filtered and washed with water (2×50 mL) and ethyl acetate (2×50mL). The solid was dried in a vacuum oven overnight to give2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide as a white solid(41.3 g, 58% yield): HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1mL/min, 240 nm, 5/95 grad to 95/5 for 5 min CH₃CN/0.1% H₃PO₄, 4.44(91%); ¹H NMR (DMSO-d₆) δ 1.98-2.17 (m, 5H, CH₂, CH₃) 2.51-2.56 (m, 1H,CHH), 2.74-2.86 (m, 1H, CHH), 4.68-4.77 (m, 1H, NCH), 5.18 (s, 2H, NH₂),6.38 (d, J=7 Hz, 1H, Ar), 6.50 (d, J=7 Hz, 1H, Ar), 6.94 (t; J=7 Hz, 1H,Ar), 8.59 (d, J=8 Hz, 1H, NH), 10.90 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ19.14, 23.75, 30.99, 49.10, 112.37, 17.21, 122.28, 128.96, 134.61,145.22, 168.36, 172.84, 173.00; LCMS: MH=262.

Step 2: A solution of2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (0.5 g, 1.9mmol) and triethyl orthopropionate (0.42 mL, 2.1 mmol) in DMF (5 mL) washeated at 150° C. in a microwave oven for 1.5 hours. To the mixture, wasadded water (30 mL). The mixture was cooled in an ice-water bath. Thesuspension was filtered to give a solid, which was stirred in methanol(15 mL) overnight. The suspension was filtered and washed with methanol(10 mL) and ethyl acetate (10 mL) to give3-(2-ethyl-5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (0.13 g, 22% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 grad 90/10 in 5 min CH₃CN/0.1%H₃PO₄, 5.74 min (98.9%); mp: 228-230° C.; ¹H NMR (DMSO-d₆) δ 1.27 (t,J=7 Hz, 3H, CH₃), 2.07-2.13 (m, 1H, CHH), 2.50 (s, 3H, CH₃), 2.51-2.65(m, 2H, 2CHH), 2.82-2.92 (m, 3H, CH₂, CHH), 5.21 (dd, J=6, 11 Hz, 1H,NCH), 7.25 (d, J=8 Hz, 1H, Ar), 7.46 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8Hz, 1H, Ar), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 11.18, 21.05, 22.48,28.02, 35.51, 55.26, 118.64, 125.00, 128.86, 133.70, 139.82, 148.27,157.69, 161.14, 169.75, 172.63; LCMS: MH=300; Anal Calcd for C₁₆H₁₇N₃O₃:C, 64.20; H, 5.72; N, 14.04. Found: C, 61.30; H, 5.34; N, 13.28.

6.14 3-(2-BUTYL-5-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide(0.65 g, 2.5 mmol) and trimethyl orthopentionate (0.66 mL, 3.8 mmol) andp-toluenesulfonic acid (140 mg) in DMF (7 mL) was heated at 150° C. in amicrowave oven for 20 minutes. The mixture was extracted with ethylacetate (50 mL) and water (50 mL). The aqueous layer was extracted withethyl acetate (50 mL). The combined organic layers was washed with water(50 mL), HCl (1N, 50 mL) and brine (50 mL). The solvent was removed invacuo to give an oil, which was purified with column chromatography(Silica Gel, methanol/methylene chloride 0% gradient to 5% 15 min), andfollowed by reversed layer column chromatography (C-18,acetonitrile/water 0% gradient to 100% 15 min) to give3-(2-butyl-5-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (80 mg, 10% yield): HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150mm, 1 mL/min, 240 nm, 10/90 grad 90/10 in 5 min CH₃CN/0.1% H₃PO₄, 6.59min (95.4%); mp: 190-192° C.; ¹H NMR (DMSO-d₆) δ 0.95 (t, J=8 Hz, 3H,CH₃), 1.40-1.49 (m, 2H, CH₂), 1.67-1.75 (m, 2H, CH₂), 2.05-2.09 (m, 1H,CHH), 2.51-2.67 (m, 3H, CH₂, CHH), 2.69 (s, 3H, CH₃), 2.81-2.90 (m, 3H,CH₂, CHH), 5.20 (dd, J=5, 11 Hz, 1H, NCH), 7.25 (d, J=7 Hz, 1H, Ar),7.44 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 13.80, 21.11, 21.72, 22.48, 28.60, 30.50, 34.42,55.41, 118.63, 124.98, 128.83, 133.70, 139.81, 148.25, 156.95, 161.17,169.75, 172.65; LCMS: MH=328; Anal Calcd for C₁₈H₂₁N₃O₃: C, 66.04; H,6.47; N, 12.84. Found: C, 65.87; H, 6.61; N, 12.89.

6.153-(5-METHYL-4-OXO-2-TRIFLUOROMETHYL-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

To a stirred suspension of2-amino-N-(2,6-dioxo-piperidin-3-yl)-6-methyl-benzamide (1.0 g, 3.8mmol) and triethylamine (1.6 mL, 11.5 mmol) in acetonitrile (20 mL) at0° C., was added trifluoroacetic anhydrous (0.9 mL, 6.4 mmol). Themixture was kept at 0° C. for 2 hours. The mixture was then heated at50° C. for 12 hours. To the mixture, was added water (50 mL). Thesuspension was filtered and washed with water (50 mL) to give a brownsolid. The solid was stirred in reagent alcohol (10 mL) for 3 hours. Thesuspension was filtered and washed with reagent alcohol (10 mL) to give3-(5-methyl-4-oxo-2-trifluoromethyl-4H-quinazolin-3-yl)-piperidine-2,6-dioneas an off-white solid (200 mg, 15% yield): HPLC: Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH₃CN/0.1% H₃PO₄, 6.39 min(98.1%); mp: 308-310° C.; ¹H NMR (DMSO-d₆) δ 2.06-2.12 (m, 1H, CHH),2.51-2.75 (m, 2H, 2CHH), 2.75 (s, 3H, CH₃), 2.89-2.99 (m, 1H, CHH), 5.12(dd, J=6, 11 Hz, 1H, NCH), 7.53 (d, J=8 Hz, 1H, Ar), 7.69 (d, J=8 Hz,1H, Ar), 7.83 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH); ¹³C NMR (DMSO-d₆)δ 21.28, 22.37, 30.23, 56.37, 117.8 (q, J_(C-F)=277 Hz), 120.05, 126.43,132.22, 134.76, 140.67, 141.31 (q, J_(C-F)=35 Hz), 145.57, 160.44,168.84, 172.46; LCMS: MH=340; Anal Calcd for C₁₅H₁₂N₃O₃F₃: C, 53.10; H,3.57; N, 12.39. Found: C, 52.92; H, 3.49; N, 12.14.

6.16 3-(5-METHYL-4-OXO-2-PHENYL-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-amino-6-methylbenzoic acid (1.0 g, 6.6 mmol) andbenzoic anhydride (3.3 g, 15 mmol) in acetonitrile (15 mL) was heated toreflux for 17 hours. The solution was allowed to cool to roomtemperature. The suspension was filtered to give a mixture of5-methyl-2-phenyl-benzo[d][1,3]oxazin-4-one and benzoic acid (1:0.4, 1.0g). The solid was used in the next step without further purification.

Step 2: A stirred suspension of solid (1.0 g) from Step 1,3-amino-piperidine-2,6-dione hydrogen chloride (0.71 g, 4.3 mmol) andtriphenyl phosphite (1.3 mL, 5.1 mmol) in pyridine (10 mL) was heated toreflux for 20 hours. To the mixture, was added Celite (1 teaspoon), andthe solvent was removed in vacuo. The resulted solid was placed in a SIMand purified by ISCO column chromatography (Silica gel, CH₃CN/CH₂Cl₂ 5%gradient to 100% in 15 min). Those tubes containing product werecollected. The solvent was removed in vacuo to give a solid, which wasstirred with reagent alcohol (30 mL) overnight. The suspension wasfiltered to give3-(5-Methyl-4-oxo-2-phenyl-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (404 mg, 27% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 35/65 CH₃CN/0.1% H₃PO₄, 6.24 min (100%);mp: 298-300° C.; ¹H NMR (DMSO-d₆) δ 2.02-2.09 (m, 1H, CHH), 2.42-2.73(m, 3H, CH₂, CHH), 2.76 (s, 3H, CH₃), 4.81 (dd, J=6, 11 Hz, 1H, NCH),7.34 (d, J=7 Hz, 1H, Ar), 7.51-7.64 (m, 6H, Ar), 7.71 (t, J=7 Hz, 1H,Ar), 10.94 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 21.14, 22.53, 30.25, 57.76,118.95, 125.47, 127.76, 128.83, 128.58, 130.05, 134.06, 134.84, 140.07,148.11, 155.92, 151.17, 159.69, 172.40; LCMS: MH=348; Anal Calcd forC₂₀H₁₇N₃O₃: C, 69.15; H, 4.93; N, 12.10. Found: C, 68.76; H, 4.81; N,12.14.

6.17 3-(5-AMINO-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: To a solution of potassium hydroxide (16.1 g, 286 mmol) in water(500 mL), was added 3-nitrophthalimide (25.0 g, 130 mmol) in portion at0° C. The suspension was stirred at 0° C. for 3 hours, and then heatedto 30° C. for 3 hours. To the solution, was added HCl (100 mL, 6N). Theresulting suspension was cooled to 0° C. for 1 hour. The suspension wasfiltered and washed with cold water (2×10 mL) to give 3-nitro-phthalamicacid as a white solid (24.6 g, 90% yield): ¹H NMR (DMSO-d₆) δ 7.69 (brs,1H, NHH), 7.74 (t, J=8 Hz, 1H, Ar), 7.92 (dd, J=1, 8 Hz, 1H, Ar), 8.13(dd, J=1, 8 Hz, 1H, Ar), 8.15 (brs, 1H, NHH), 13.59 (s, 1H, OH); ¹³C NMR(DMSO-d₆) δ 125.33, 129.15, 130.25, 132.54, 136.72, 147.03, 165.90,167.31.

Step 2: To a mixture of 3-nitro-phthalamic acid (24.6 g, 117 mmol) andpotassium hydroxide (6.56 g, 117 mmol) in water (118 mL), was added amixture of bromine (6 mL), potassium hydroxide (13.2 g, 234 mmol) inwater (240 mL) at 0° C., followed by addition of a solution of potassiumhydroxide (19.8 g, 351 mmol) in water (350 mL). After 5 minutes at 0°C., the mixture was heated in a 100° C. oil bath for 1 hour. Thereaction solution was cooled to room temperature, and then, in anice-water bath for 30 minutes. To the mixture, a solution of HCl (240mL, 2N) was added dropwise at 0° C., and the resulting mixture was keptfor 1 hour. The suspension was filtered and washed with water (5 mL) togive 2-amino-6-nitro-benzoic acid as yellow solid (15.6 g, 73% yield):HPLC: Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm,CH₃CN/0.1% H₃PO₄, 5% grad to 95% over 5 min, 5.83 min (85%); ¹H NMR(DMSO-d₆) δ 6.90 (dd, J=1, 8 Hz, 1H, Ar), 7.01 (dd, J=1, 9 Hz, 1H, Ar),7.31 (t, J=8 Hz, 1H, Ar), 8.5-9.5 (brs, 3H, OH, NH₂); ¹³C NMR (DMSO-d₆)δ 105.58, 110.14, 120.07, 131.74, 149.80, 151.36, 166.30; LCMS: MH=183.

Step 3: A mixture of 2-amino-6-nitro-benzoic acid (1.5 g, 8.2 mmol) inacetic anhydride (15 mL) was heated at 200° C. for 30 minutes in amicrowave oven. The mixture was filtered and washed with ethyl acetate(20 mL). The filtrate was concentrated in vacuo. The solid was stirredin ether (20 mL) for 2 hours. The suspension was filtered and washedwith ether (20 mL) to give 2-methyl-5-nitro-benzo[d][1,3]oxazin-4-one asa light brown solid (1.4 g, 85% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, CH₃CN/0.1% H₃PO₄, 5% grad 95% in 5 min,5.36 min (92%); ¹H NMR (DMSO-d₆) δ 2.42 (s, 3H, CH₃), 7.79 (dd, J=1, 8Hz, 1H, Ar), 7.93 (dd, J=1, 8 Hz, 1H, Ar), 8.06 (t, J=8 Hz, 1H, Ar); ¹³CNMR (DMSO-d₆) δ 20.87, 107.79, 121.54, 128.87, 137.19, 147.12, 148.46,155.18, 161.78; LCMS: MH=207.

Step 4: Two vials each with a suspension of5-nitro-2-methyl-benzo[d][1,3]oxazin-4-one (0.60 g, 2.91 mmol) and3-amino-piperidine-2,6-dione hydrogen chloride (0.48 g, 2.91 mmol) inpyridine (15 mL) were heated at 170° C. for 10 minutes in a microwaveoven. The suspension was filtered and washed with pyridine (5 mL). Thefiltrate was concentrated in vacuo. The resulting mixture was stirred inHCl (30 mL, 1N), ethyl acetate (15 mL) and ether (15 mL) for 2 hours.The suspension was filtered and washed with water (30 mL) and ethylacetate (30 mL) to give a dark brown solid, which was stirred withmethanol (50 mL) at room temperature overnight. The suspension wasfiltered and washed with methanol to give3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as ablack solid (490 mg, 27% yield). The solid was used in the next stepwithout further purification.

Step 5: A mixture of3-(2-methyl-5-nitro-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (250mg) and Pd(OH)₂ on carbon (110 mg) in DMF (40 mL) was shaken underhydrogen (50 psi) for 12 hours. The suspension was filtered through apad of Celite and washed with DMF (10 mL). The filtrate was concentratedin vacuo and the resulting oil was purified by flash columnchromatography (silica gel, methanol/methylene chloride) to give3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as awhite solid (156 mg, 69% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, 3.52 min (99.9%);mp: 293-295° C.; ¹H NMR (DMSO-d₆) δ 2.10-2.17 (m, 1H, CHH), 2.53 (s, 3H,CH₃), 2.59-2.69 (m, 2H, CH₂), 2.76-2.89 (m, 1H, CHH), 5.14 (dd, J=6, 11Hz, 1H, NCH), 6.56 (d, J=8 Hz, 1H, Ar), 6.59 (d, J=8 Hz, 1H, Ar), 7.02(s, 2H, NH₂), 7.36 (t, J=8 Hz, 1H, Ar), 10.98 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.98, 23.14, 30.52, 55.92, 104.15, 110.48, 111.37, 134.92,148.17, 150.55, 153.62, 162.59, 169.65, 172.57; LCMS: MH=287; Anal.Calcd. for C₁₄H₁₄N₄O₃+0.3 H₂O: C, 57.65; H, 5.05; N, 19.21. Found: C,57.50; H, 4.73; N, 19.00.

6.18(S)-3-(5-AMINO-2-METHYL-4-OXOQUINAZOLIN-3(4H)-YL)-3-METHYLPIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one (2.0g, 9.7 mmol), (S)-3-amino-3-methylpiperidine-2,6-dione hydrobromide (2.2g, 9.7 mmol), imidazole (1.5 g, 21 mmol), and triphenylphosphite (3.7 g,12 mmol) in DMF (20 mL) was stirred under nitrogen at 45° C. for 40hours. The mixture was evaporated, and the residue was chromatographedon silica gel using a dichloromethane-acetonitrile gradient. The producteluted at 15% acetonitrile, providing(S)-3-methyl-3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dioneas a yellow solid (0.70 g, 22% yield); ¹H NMR (DMSO-d₆) δ 1.94 (s, 3H,CH₃), 2.35-2.40 (m, 1H, CHH), 2.45-2.59 (m, 2H, 2CHH), 2.71-2.83 (m, 4H,CH₃, CHH), 7.75-7.82 (m, 2H, Ar), 7.95 (dd, J=8, 8 Hz, 1H, Ar), 10.86(s, 1H, NH).

Step 2: A mixture of(S)-3-methyl-3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione(0.30 g, 1.0 mmol) and 10% Pd—C (0.2 g, 50% wet), in 200 mL of 3:1 ethylacetate-methanol was shaken under 50 psi H₂ for 45 minutes. The mixturewas filtered through Celite, and the solvent was evaporated. The residuewas redissolved in 200 mL of 4:1 dichloromethane-acetone, and manganesedioxide (0.20 g, 2.2 mmol) was added. This mixture was stirred for 16hours. The mixture was filtered through Celite, and the filtrate wasevaporated. The residue was chromatographed on silica gel using adichloromethane-acetonitrile gradient, eluting(S)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-3-methylpiperidine-2,6-dioneas a beige solid (0.10 g, 37% yield): HPLC, Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 1.63(99.20%); mp 297-299° C.; ¹H NMR (DMSO-d₆) δ 1.88 (s, 3H, CH₃),2.31-2.36 (m, 1H, CHH), 2.53-2.59 (m, 2H, 2CHH), 2.62 (s, 3H, CH₃),2.71-2.84 (m, 1H, CHH), 6.53-6.56 (m, 2H, Ar), 6.95 (br, 2H, NH₂), 7.35(t, J=8 Hz, 1H, Ar), 10.72 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 24.5, 26.3,28.3, 29.0, 62.2, 104.2, 110.5, 110.8, 135.0, 147.4, 150.4, 152.9,164.9, 171.5, 173.0; Anal. Calcd for C₁₅H₁₆N₄O₃: C, 59.99; H, 5.37; N,18.66. Found: C, 59.61; H, 5.43; N, 18.59.

6.19(R)-3-(5-AMINO-2-METHYL-4-OXOQUINAZOLIN-3(4H)-YL)-3-METHYLPIPERIDINE-2,6-DIONE

Step 1: A mixture of 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one (2.0g, 9.7 mmol), (R)-3-amino-3-methylpiperidine-2,6-dione hydrobromide (2.2g, 9.7 mmol), imidazole (1.5 g, 21 mmol), and triphenylphosphite (3.7 g,12 mmol) in DMF (20 mL) was stirred under nitrogen at 45° C. for 40hours. The mixture was evaporated, and the residue was chromatographedon silica gel using a dichloromethane-acetonitrile gradient. The producteluted at 60% acetonitrile, providing(R)-3-methyl-3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dioneas a yellow solid (0.60 g, 19% yield); ¹H NMR (DMSO-d₆) δ 1.94 (s, 3H,CH₃), 2.35-2.40 (m, 1H, CHH), 2.45-2.59 (m, 2H, 2CHH), 2.71-2.83 (m, 4H,CH₃, CHH), 7.75-7.82 (m, 2H, Ar), 7.95 (dd, J=8, 8 Hz, 1H, Ar), 10.86(s, 1H, NH).

Step 2: A mixture of(R)-3-methyl-3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione(0.40 g, 1.2 mmol) and 10% Pd—C (0.2 g, 50% wet), in 200 mL of 3:1 ethylacetate-methanol was shaken under 50 psi H₂ for 3 hours. The mixture wasfiltered through Celite, and the solvent was evaporated. The residue waschromatographed on silica gel using a dichloromethane-acetonitrilegradient, providing(R)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-3-methylpiperidine-2,6-dioneas an off-white solid (0.16 g 44% yield): HPLC, Waters Symmetry C-18,3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 1.62(98.71%); mp 295-297° C.; ¹H NMR (DMSO-d₆) δ 1.88 (s, 3H, CH₃),2.31-2.36 (m, 1H, CHH), 2.53-2.59 (m, 2H, 2CHH), 2.62 (s, 3H, CH₃),2.71-2.84 (m, 1H, CHH), 6.53-6.56 (m, 2H, Ar), 6.95 (br, 2H, NH₂), 7.35(t, J=8 Hz, 1H, Ar), 10.72 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 24.5, 26.3,28.3, 29.0, 62.2, 104.2, 110.5, 110.8, 135.0, 147.4, 150.4, 152.9,164.9, 171.5, 173.0; Anal. Calcd for C₁₅H₁₆N₄O₃: C, 59.99; H, 5.37; N,18.66. Found: C, 59.73; H, 5.26; N, 18.69.

6.20N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YL]-2-METHOXY-ACETAMIDE

To a stirred mixture of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.11g, 0.35 mmol) in tetrahydrofuran (4 mL), was added methoxyacetylchloride (0.06 mL, 0.70 mmol) and heated at 80° C. for one hour. Themixture was quenched with a few drops of methanol. The solvent wasevaporated, and the residue was purified by flash column chromatography(Silica gel, methanol/methylene chloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-2-methoxy-acetamide(44 mg, 35% yield) as a white solid; HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 6.77 min (96.3%); mp, 282-284° C.; ¹HNMR(DMSO-d₆) δ 2.20-2.22 (m, 1H, CHH), 2.60-2.85 (m, 6H, CHCH₂, CH₃), 3.40(s, 3H, ° C. H₃), 4.04 (s, 2H, ° C. H₂), 5.30 (dd, J=6, 11 Hz, 1H, CH),7.30-8.64 (m, 3H, Ar), 11.09 (s, 1H, NH), 12.31 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.77, 23.31, 30.62, 56.71, 59.04, 71.88, 107.95, 115.39,120.94, 135.51, 138.89, 147.90, 154.84, 162.69, 169.12, 169.34, 172.64.LCMS MH=359; Anal Calcd For C₇H₁₈N₄O₅+0.7 H₂O: C, 55.04; H, 5.27; N,15.10. Found: C, 54.75; H, 5.32; N, 14.91.

6.21N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YL]-ACETAMIDE

To a stirred mixture of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.45g, 1.5 mmol) in tetrahydrofuran (10 mL), was added acetyl chloride (0.63mL, 8.8 mmol) and heated at 80° C. for one hour. The mixture wasquenched with a few drops of methanol. The solvent was evaporated, andthe residue was purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide(80 mg, 16% yield); HPLC, Waters Symmetry C₁₈, 5 μm, 3.9×150 mm, 1mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5 in 5 min, keptfor 5 min, 5.15 min (98.6%); mp, 320-322° C.; ¹HNMR (DMSO-d₆)

2.16 (s, 3H, CH₃), 2.18-2.24 (m, 1H, CHH), 2.59-2.90 (m, 6H, CHCH₂,CH₃), 5.32 (dd, J=6, 11 Hz, 1H, CH), 7.28-8.54 (m, 3H, Ar), 11.08 (s,1H, NH), 11.70 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.65, 23.35, 25.29,30.57, 56.71, 107.39, 115.09, 120.38, 135.63, 139.84, 147.84, 154.71,163.01, 168.67, 169.29, 172.60. LCMS MH=329; Anal Calcd ForC₁₆H₁₆N₄O₄+2.2 H₂O: C, 52.23; H, 5.59; N, 15.23. Found: C, 52.20; H,5.57; N, 15.21.

6.22N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YL]-CYCLOPROPANECARBOXAMIDE

To a stirred mixture of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.41g, 1.3 mmol) in tetrahydrofuran (8 mL), was added cyclopropanecarbonylchloride (0.24 mL, 2.7 mmol) and heated at 80° C. for one hour. Themixture was quenched with a few drops of methanol. The solvent wasevaporated and the residue was purified by flash column chromatography(Silica gel, methanol/methylene chloride 4%/96%) to give2-cyclopropyl-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamideas a white solid (110 mg, 23% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 35/65 CH₃CN/0.1% H₃PO₄, 2.78 min (98.2%);mp, 239-241° C.; ¹HNMR (DMSO-d₆) δ 0.87 (d, J=5 Hz, 4H, CH₂CH₂),1.70-1.75 (q, J=6 Hz, 1H, CH), 2.20-2.25 (m, 1H, CHH), 2.59-2.88 (m, 5H,CH₂, CH₃), 5.33 (dd, J=6, 12 Hz, 1H, CH), 7.26-8.52 (m, 3H, Ar), 11.10(s, 1H, NH), 12.03 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 7.88, 7.99, 16.26,20.68, 23.34, 30.56, 56.73, 115.24, 120.29, 135.64, 139.80, 147.85,154.72, 163.14, 169.34, 171.92, 172.60. LCMS MH=355; Anal Calcd ForC₁₈H₁₈N₄O₄+1.7 H₂O: C, 56.16; H, 5.60; N, 14.55. Found: C, 55.90; H,5.50; N, 14.31.

6.23 HEPTANOIC ACID[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YL]-AMIDE

To a stirred mixture of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.49g, 1.6 mmol) in tetrahydrofuran (10 mL), was added heptanoyl chloride(0.88 mL, 5.7 mmol) and heated at 80° C. for two hours. The mixture wasquenched with a few drops of methanol. The solvent was evaporated, andthe residue was purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to give heptanoic acid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-amideas a white solid (120 mg, 18% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 7.12 min (95.5%); mp, 230-232° C.; ¹HNMR(DMSO-d₆) δ 0.86 (t, J=7 Hz, 3H, CH₃), 1.24-1.36 (m, 6H, 3CH₂),1.56-1.65 (m, 2H, CH₂), 2.18-2.23 (m, 1H, CHH), 2.40 (t, J=7 Hz, 2H,CH₂), 2.59-2.88 (m, 6H, CHCH₂, CH₃), 5.32 (dd, J=6, 11 Hz, 1H, CH),7.26-8.55 (m, 3H, Ar), 11.09 (s, 1H, NH), 11.74 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 13.87, 20.65, 21.89, 23.35, 24.66, 28.05, 30.60, 30.95,37.64, 56.73, 107.43, 115.12, 120.32, 135.63, 139.85, 147.86, 154.71,163.07, 169.28, 171.51, 172.57. LCMS MH=399; Anal Calcd ForC₂₁H₂₆N₄O₄+0.3 H₂O: C, 62.45; H, 6.64; N, 13.87. Found: C, 62.28; H,6.66; N, 13.61.

6.24N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YL]-2-ETHOXY-ACETAMIDE

To a stirred solution of ethoxyacetic acid (0.39 mL, 4.2 mmol), oxalylchloride (0.34 mL, 3.9 mmol) in diethylether (3 mL) was added DMF (0.02mL). The mixture was stirred at room temp for two hours, followed byaddition of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.60g, 2.0 mmol) and tetrahydrofuran (20 mL). The mixture was refluxedovernight and then cooled and quenched by methanol (˜5 mL). The solventwas evaporated, and the residue was purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-2-ethoxy-acetamideas a white solid (90 mg, 12% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 5.75 min (99.6%); mp, 291-293° C.; ¹HNMR(DMSO-d₆) δ 1.23 (t, J=6 Hz, 3H, CH₂CH₃), 2.18-2.25 (m, 1H, CHH),2.58-2.92 (m, 6H, CHCH₂, CH₃), 3.57 (q, J=7 Hz, 2H, CH₂CH₃), 4.01-4.12(dd, J=16 Hz, 2H, CH₂O), 5.30 (dd, J=6, 11 Hz, 1H, CH), 7.30-8.64 (m,3H, Ar), 11.07 (s, 1H, NH), 12.52 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ14.61, 20.81, 23.25, 30.52, 56.64, 67.05, 70.09, 107.95, 115.13, 120.83,135.55, 138.97, 147.90, 154.80, 162.61, 169.38, 169.54, 172.51. LCMSMH=373; Anal Calcd For C₁₈H₂₀N₄O₅: C, 58.06; H, 5.41; N, 15.05. Found:C, 57.83; H, 5.37; N, 14.92.

6.252-DIMETHYLAMINO-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YL]-ACETAMIDEHYDROGEN CHLORIDE

To a stirred suspension of2-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamide(0.75 g, 2.1 mmol) in DMF (3 mL), was added dimethylamine in THF (3.6mL, 2N, 7.2 mmol) at room temperature. After 2 days, sodium hydrogencarbonate (sat, 10 mL) and water (10 mL) were added to the mixture.After 1 hour, the suspension was filtered and washed with water (5 mL)to give a white solid. To the stirred suspension of above solid inmethylene chloride (20 mL), was added HCl in ether (2 mL, 2N, 4 mmol) atroom temperature. After 18 hours, the suspension was filtered and washedwith methylene chloride (2×20 mL) to give2-dimethylamino-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamidehydrogen chloride as a white solid (0.72 g, 85% yield): HPLC: WatersSymmetry C₁₈, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1%H₃PO₄, 2.50 min (62.2%) and 2.71 (37.7%); mp: 256-258° C.; ¹H NMR(DMSO-d₆) δ 2.21-2.28 (m, 1H, CHH), 2.61-2.70 (m, 2H, 2CHH), 2.73 (s,3H, CH₃), 2.88 (s, 6H, 2CH₃), 2.93-3.00 (m, 1H, CHH), 4.40 (d, J=4 Hz,2H, CH₂), 5.44 (dd, J=6, 11 Hz, 1H, NCH), 7.45 (dd, J=1, 8 Hz, 1H, Ar),7.88 (t, J=8 Hz, 1H, Ar), 8.46 (dd, J=1, 8 Hz, 1H, Ar), 10.48 (brs, 1H,HCl), 11.11 (s, 1H, NH), 11.50 (brs, 1H, HCl), 11.86 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 20.57, 23.04, 30.52, 43.16, 56.83, 58.16, 107.98,116.49, 120.95, 135.94, 138.34, 146.82, 155.92, 162.45 163.75, 169.02,172.63; LCMS: MH=372; Anal Calcd for C₁₈H₂₁N₅O₄+1.8 HCl+0.5 H₂O: C,48.47; H, 5.38; N, 15.70; Cl, 14.31. Found: C, 48.34; H, 5.03; N, 15.39;Cl, 14.03.

6.262-CHLORO-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YL]-ACETAMIDE

The stirred mixture of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (4.0g, 14 mmol) and chloroacetyl chloride (7.7 mL, 98 mmol) was heated in a100° C. oil bath for 15 minutes. The mixture was allowed to cool to roomtemperature. Acetonitrile (5 mL) was added to the mixture. Thesuspension was filtered and washed with ethyl acetate (2×10 mL) to givea white solid. The solid was stirred in methanol (50 mL) overnight. Thesuspension was filtered and washed with methanol (20 mL) to give2-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-acetamideas a white solid (4.5 g, 90% yield): HPLC: Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH₃CN/0.1% H₃PO₄, 12.79 min (97.6%);mp: 275-277° C.; ¹H NMR (DMSO-d₆) δ 2.18-2.25 (m, 1H, CHH), 2.61-2.80(m, 5H, CH₃, 2CHH), 2.86-2.91 (m, 1H, CHH), 4.48-4.53 (m, 2H, CH₂), 5.36(dd, J=6, 11 Hz, 1H, NCH), 7.39 (dd, J=1, 8 Hz, 1H, Ar), 7.83 (t, J=8Hz, 1H, Ar), 8.57 (dd, J=1, 8 Hz, 1H, Ar), 10.7 (brs, 1H, HCl), 11.11(s, 1H, NH), 12.26 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.66, 23.10, 30.60,43.56, 56.84, 107.89, 115.65, 120.87, 135.77, 138.87, 147.17, 155.49,162.67, 165.55, 169.14.172.60; LCMS: MH=363, 365; Anal Calcd forC₁₆H₁₅N₄O₄Cl+1.05 HCl: C, 47.92; H, 4.03; N, 13.97; Cl, 18.12. Found: C,48.24; H, 3.79; N, 13.84; Cl, 18.27.

6.27[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YL]-CARBAMICACID ETHYL ESTER

To a stirred mixture of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.41g, 1.3 mmol) in tetrahydrofuran (10 mL), was added ethyl chloroformate(0.45 mL, 4.7 mmol) and heated at 80° C. for three hours. The mixturewas quenched with a few drops of methanol. The solvent was evaporated,and the residue was purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to give[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-carbamicacid ethyl ester as a white solid (130 mg, 27% yield); HPLC, WatersSymmetry C₁₈, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1%H₃PO₄, gradient to 95/5 in 5 min, kept for 5 min, 6.26 min (99.2%); mp,284-286° C. (decomposed); ¹HNMR (DMSO-d₆)

1.26 (t, J=7 Hz, 3H, CH₂CH₃), 2.15-2.19 (m, 1H, CHH), 2.58-2.90 (m, 6H,CHCH₂, CH₃), 4.16 (q, J=7 Hz, 2H, CH₂CH₃), 5.31 (dd, J=6, 11 Hz, 1H,CH), 7.23-8.24 (m, 3H, Ar), 11.08 (s, 1H, NH), 11.30 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 14.28, 20.72, 23.28, 30.53, 56.70, 60.99, 107.14,113.36, 119.59, 135.73, 140.00, 147.95, 152.66, 154.73, 169.31, 172.54.LCMS MH=359; Anal Calcd For C₁₇H₁₈N₄O₅+0.8 H₂O: C, 54.78; H, 5.30; N,15.03. Found: C, 54.67; H, 4.99; N, 14.80.

6.28[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-CARBAMICACID TERT-BUTYL ESTER

Step 1: A mixture of 2-methyl-6-nitro-benzoic acid methyl ester (99 g,508 mmol), 1,3-dibromo-5,5-dimethylhydantoin (DBH) (80 g, 279 mmol), inmethyl acetate (600 mL) was heated at 78° C. for 40 minutes, whilestirred with a mechanical stirrer. Then a solution of2,2′-azobisisobutyro-nitrile (AlBN) (4.2 g, 25 mmol) in methyl acetate(80 mL) was added and heated at 75° C. for 11 hours. The mixture wasallowed to cool to 15° C. and stirred for 2 hours to age theprecipitate. The suspension was filtered, washed with 10° C. methylacetate (2×50 mL) to give a brown filtrate. To the filtrate, was addedheptane (500 mL). The solution was washed with 2% brine (2×500 mL) andwater (2×500 mL). The organic layer was concentrated to about 2 volumes,added t-butyl methyl ether (300 mL), heated at 70° C. for 15 minutes,cooled the solution to 53° C. over one hour, seeded with the product(about 250 mg) at 45° C., then at 20˜25° C., while blowing nitrogen witha glass pipette overnight. The resulting suspension was filtered via amedium pore-sized funnel, washed with a pre-cooled 10° C. mixed solventof heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight togive 2-bromomethyl-6-nitro-benzoic acid methyl ester as an off-whitesolid (49 g, 35% yield). The solid was used in the next step withoutfurther purification.

Step 2: A stirred mixture of 2-bromomethyl-6-nitro-benzoic acid methylester (36.6 g, 134 mmol), di-tert-butyl iminodicarboxylate (29.1 g, 134mmol), cesium carbonate (89.3 g, 274 mmol), and lithium iodide (0.89 g,6.7 mmol) in 2-butanone (400 mL) was heated to reflux in a 100° C. oilbath for 12 hours while stirred with a mechanical stirrer. The mixturewas allowed to cool to room temperature. To the mixture, was add brine(300 mL), water (300 mL), ethyl acetate (750 mL) and stirred for 10minutes, then the suspension was filtered through a pad of Celite. Thetwo layers were separated, and the organic layer was evaporated to aless volume and the aqueous layer was extracted with ethyl acetate(2×150 mL). The combined organic layers were washed with brine (500 mL),dried over magnesium sulfate while de-colored at the same time withcharcoal at room temp for 30 minutes. The black mixture was filteredthrough a pad of Celite. The filtrate was evaporated to give2-(di-tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid methyl esteras a brown oil (51.53 g, 94% yield). The product was used in the nextstep without further purification.

Step 3: To a stirred brown solution of2-(di-tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid methyl ester(51.53 g, 126 mmol) in methylene chloride (600 mL), was addedtrifluoroacetic acid (18.2 mL, 245 mmol), and the mixture was stirred atroom temp overnight. Sat. sodium bicarbonate (400 mL) was added to thesolution, and the mixture was stirred for 10 minutes. The organic layerwas separated, dried over magnesium sulfate and evaporated to give2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid methyl ester asa brown oil (41.4 g, 106% crude yield). The product was used in the nextstep without further purification.

Step 4: A mixture of 2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoicacid methyl ester (38.96 g, 126 mmol) lithium hydroxide (3.61 g, 151mmol) in methanol (450 mL) and water (225 mL) was stirred with amechanical stirrer at room temp overnight. The methanol was evaporatedand to the aqueous solution, was added 1 N HCl (200 mL) to form theprecipitate. Ether (300 mL) was added, and the mixture was stirred at 0°C. for 2 hours. The suspension was filtered, washed with water (100 mL)and ether (100 mL), and suction dried in hood overnight to give2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoic acid as a yellowsolid (22.4 g, 60% yield). The product was used in the next step withoutfurther purification.

Step 5: A mixture of 2-(tert-butoxycarbonylamino-methyl)-6-nitro-benzoicacid (2.19 g, 75 mmol) in methanol (530 mL) and palladium/carbon (0.2 g)was hydrogenated with a Parr-shaker overnight at 51 psi. The blackmixture was filtered through a pad of Celite, and the filtrate wasevaporated to give a foamy brown oil, which was stirred in ether (300mL) overnight. The suspension was filtered to give2-amino-6-(tert-butoxycarbonylamino-methyl)-benzoic acid as a yellowsolid (13.0 g, 65% yield). The product was used in the next step withoutfurther purification.

Step 6: To a stirred solution of2-amino-6-(tert-butoxycarbonylamino-methyl)-benzoic acid (13.0 g, 48.8mmol), imidazole (3.99 g, 58.6 mmol) in acetonitrile (160 mL), was addedacetyl chloride (4.18 mL, 58.6 mmol), and the mixture was stirred atroom temp overnight. To the mixture,e was added3-amino-piperidine-2,6-dione hydrogen chloride (8.03 g, 48.8 mmol),imidazole (6.65 g, 97.6 mmol) and triphenyl phosphite (15.4 mL, 58.6mmol), and the mixture was heated to reflux for 6 hours. The mixture wascooled to room temperature, and water (500 mL) was added. The suspensionwas filtered, washed with water (50 mL), ethyl acetate (20 mL), ether(50 mL), and suction dried to give[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-carbamicacid tert-butyl ester as a brown solid (10.5 g, 54% yield): HPLC: WatersSymmetry C₁₈, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH₃CN/0.1%H₃PO₄, 5.50 min (98.5%); mp: 206-208° C.; ¹H NMR (DMSO-d₆) δ 1.40 (s,9H, 3CH₃), 2.15-2.20 (m, 1H, CHH), 2.55-2.68 (m, 5H, CH₃, 2CHH),2.79-2.86 (m, 1H, CHH), 4.63-4367 (m, 2H, CH₂), 5.22 (dd, J=6, 11 Hz,1H, NCH), 7.20 (t, J=6 Hz, 1H, NH), 7.32 (d, J=8 Hz, 1H, Ar), 7.48 (d,J=8 Hz, 1H, Ar), 7.76 (t, J=8 Hz, 1H, Ar), 11.02 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.79, 23.27, 28.19, 30.57, 42.82, 56.47, 77.91, 117.53,123.86, 125.33, 133.92, 141.76, 148.44, 154.76, 155.67, 161.01, 169.51,172.59; LCMS: MH=401; Anal Calcd for C₂₀H₂₄N₄O₅+0.5 H₂O: C, 58.67; H,6.15; N, 13.68. Found: C, 58.45; H, 5.88; N, 13.34.

6.293-(5-AMINOMETHYL-2-METHYL-4-OXO-4H-QUINAZOLIN-3-YL)-PIPERIDINE-2,6-DIONE

Step 1: To a stirred brown solution of[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-carbamicacid tert-butyl ester (10.4 g, 25.9 mmol) in methanol (108 mL) andmethylene chloride (108 mL), was added 2 M HCl in ether (304 mL), andthe mixture was stirred overnight. Solvent was evaporated, and theresidue was stirred in ether (200 mL) for 2 hours. The suspension wasfiltered to give3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride as a light yellow solid (8.9 g, 102% crude yield). Theproduct was used in the next step without further purification.

Step 2:3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (1.0 g) was stirred in iso-propanol (10 mL) overnight,and the suspension was filtered. The resulting solid was further stirredin methanol (10 mL) overnight, and the suspension was filtered. Thesolid was dissolved in pure water (60 mL), and the solution was washedwith ethyl acetate (2×100 mL). The aqueous was evaporated to give3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride as an off-white solid (0.35 g, 35% yield); HPLC,Waters Xterra RP 18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, Waters LCModule 1, 05/95 CH₃CN/0.1% (HCO₂)NH_(4,) 8.04 min (99.9%); mp, 256° C.(decomposed); ¹HNMR (DMSO-d₆)

2.14-2.20 (m, 1H, CHH), 2.58-2.92 (m, 6H, CHCH₂, CH₃), 4.25-4.32 (m, 1H,NHCHH), 4.58-4.64 (m, 1H, NHCHH), 5.33 (dd, J=6, 11 Hz, 1H, CH),7.53-7.89 (m, 3H, Ar), 8.31 (brs, 3H, ClNH₃), 11.06 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.58, 23.15, 30.508, 41.38, 56.64, 118.38, 127.51, 129.25,134.20, 134.33, 147.86, 155.63, 160.86, 169.26, 172.59. LCMS MH=301;Anal Calcd For C₁₅H₁₇N₄O₃Cl+0.5 H₂O and +0.55 HCl: C, 49.25; H, 5.11; N,15.31; Cl, 15.02. Found: C, 49.23; H, 5.00; N, 15.24; Cl, 14.97.

6.30N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-ACETAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.65 g, 1.9 mmol) in acetonitrile (10 mL), was addedacetyl chloride (0.13 mL, 1.8 mmol) and N,N-diisopropyl ethylamine (0.70mL, 4.3 mmol). The mixture was stirred at room temp for 15 minutes. Thesolvent was evaporated, and the residue was purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamideas a light yellow solid (104 mg, 16% yield); HPLC, Waters Symmetry C₁₈,5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 3.93 min (99.0%); mp, 293-291° C.; ¹HNMR(DMSO-d₆)

1.92 (s, 3H, CH₃), 2.14-2.20 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH₂,CH₃), 4.73-4.77 (m, 2H, CH₂NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.31-7.76(m, 3H, Ar), 8.22 (t, J=6 Hz, 1H, CH₂NH); ¹³C NMR (DMSO-d₆) δ 20.78,22.60, 23.26, 30.58, 41.49, 56.48, 117.65, 124.48, 125.42, 133.83,141.06, 148.44, 154.75, 160.95, 169.32, 169.51, 172.58. LCMS MH=343;Anal Calcd For C₁₇H₁₈N₄O₄: C, 59.64; H, 5.30; N, 16.37. Found: C, 59.46;H, 5.05; N, 16.24.

6.31N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-BUTYRAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.53 g, 1.6 mmol) in acetonitrile (10 mL), was addedbutyryl chloride (0.25 mL, 2.4 mmol) and N,N-diisopropyl ethylamine(0.65 mL, 3.9 mmol). The mixture was stirred at room temp for 15minutes. The solvent was evaporated, and the residue was purified byflash column chromatography (Silica gel, methanol/methylene chloride4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-butyramideas a light yellow solid (270 mg, 46% yield); HPLC, Waters Symmetry C₁₈,5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 5.18 min (98.6%); mp, 250-252° C.; ¹HNMR(DMSO-d₆)

0.88 (t, J=7 Hz, 3H, CH₃), 1.56 (m, J=7 Hz, 2H, CH₂CH₂CH₃), 2.15-2.20(m, 3H, CH₂, CHH), 2.57-2.89 (m, 6H, CHCH₂, CH₃), 4.77-4.85 (m, 2H,CH₂NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.30-7.76 (m, 3H, Ar), 8.18 (t,J=5 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 13.65, 18.67,20.77, 23.27, 30.58, 37.32, 41.39, 56.47, 117.63, 124.28, 125.38,133.83, 141.23, 148.44, 154.76, 160.95, 169.51, 172.14, 172.60. LCMSMH=371; Anal Calcd For C₁₉H₂₂N₄O₄: C, 61.61; H, 5.99; N, 15.13. Found:C, 61.49; H, 5.76; N, 15.00.

6.32 HEPTANOIC ACID[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-AMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was addedheptanoyl chloride (0.34 mL, 2.2 mmol) and N,N-diisopropyl ethylamine(0.60 mL, 3.7 mmol). The mixture was stirred at room temp for 15minutes. The solvent was evaporated, and the residue was purified byflash column chromatography (Silica gel, methanol/methylene chloride4%/96%) to give heptanoic acid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amideas a light yellow solid (280 mg, 47% yield); HPLC, Waters Symmetry C₁₈,5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 6.10 min (97.8%); mp, 208-210° C.; ¹HNMR(DMSO-d₆)

0.86 (t, J=6 Hz, 3H, CH₃), 1.25-2.21 (m, 11H, CH₂CH₂CH₂CH₂CH₂, CHH),2.57-2.89 (m, 6H, CHCH₂, CH₃), 4.68-4.84 (m, 2H, CH₂NH), 5.23 (dd, J=6,12 Hz, 1H, CH), 7.29-7.75 (m, 3H, Ar), 8.18 (t, J=6 Hz, 1H, CH₂NH),11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 13.87, 20.77, 21.98, 23.27,25.22, 28.31, 30.59, 31.96, 35.37, 38.68, 38.96, 39.23, 39.51, 39.79,40.07, 40.35, 41.39, 56.47, 117.63, 124.30, 125.39, 133.78, 141.23,148.44, 154.75, 160.95, 169.51, 172.29, 172.59. LCMS MH=413; Anal CalcdFor C₂₂H₂₈N₄O₄: C, 64.06; H, 6.84; N, 13.58. Found: C, 64.05; H, 6.80;N, 13.58.

6.33N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-3,3-DIMETHYL-BUTYRAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was addedt-butylacetyl chloride (0.31 mL, 2.2 mmol) and N,N-diisopropylethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room temp for15 minutes. The solvent was evaporated, and the residue was purified byflash column chromatography (Silica gel, methanol/methylene chloride4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3,3-dimethyl-butyramideas a light yellow solid (120 mg, 22% yield); HPLC, Waters Symmetry C₁₈,5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 5.74 min (98.4%); mp, 212-214° C.; ¹HNMR(DMSO-d₆)

0.96 (s, 9H, 3CH₃), 2.08 (s, 2H, CH₂Me₃), 2.12-2.19 (m, 1H, CHH),2.57-2.86 (m, 6H, CHCH₂, CH₃), 4.68-4.85 (m, 2H, CH₂NH), 5.24 (dd, J=6,11 Hz, 1H, CH), 7.34-7.76 (m, 3H, Ar), 8.11 (t, J=6 Hz, 1H, CH₂NH),11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.76, 23.28, 29.69, 30.47,30.58, 41.43, 48.76, 56.47, 117.65, 124.64, 125.42, 133.77, 141.19,148.42, 154.75, 160.93, 169.51, 170.97, 172.60. LCMS MH=399; Anal CalcdFor C₂₁H₂₆N₄O₄+0.1 H₂O: C, 63.02; H, 6.60; N, 14.00. Found: C, 62.86; H,6.70; N, 13.92.

6.34 CYCLOPROPANECARBOXYLIC ACID[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-AMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.53 g, 1.6 mmol) in acetonitrile (10 mL), was addedcyclopropane carboxylic acid chloride (0.16 mL, 1.7 mmol) andN,N-diisopropyl ethylamine (0.59 mL, 3.6 mmol). The mixture was stirredat room temp for 15 minutes. The solvent was evaporated, and the residuewas purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to give cyclopropanecarboxylic acid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amideas an off-white solid (310 mg, 54% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 5.50 min (98.6%); mp, decomposed at 298°C.; ¹HNMR (DMSO-d₆)

0.67-0.70 (m, 4H, cyclo-CH₂CH₂), 1.65-1.73 (m, 1H, cyclo-CH), 2.11-2.20(m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH₂, CH₃), 4.77-4.87 (m, 2H, CH₂NH),5.23 (dd, J=6, 12 Hz, 1H, CH), 7.31-7.78 (m, 3H, Ar), 8.44 (t, J=6 Hz,1H, CH₂NH), 11.02 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 6.28, 13.57, 20.76,23.28, 30.58, 41.53, 56.47, 117.65, 124.50, 125.44, 133.89, 141.14,148.44, 154.77, 160.94, 169.53, 172.60, 172.73. LCMS MH=369; Anal CalcdFor C₁₉H₂₀N₄O₄+0.1 H₂O: C, 61.65; H, 5.50; N, 15.13. Found: C, 61.48; H,5.47; N, 14.97.

6.352-DIMETHYLAMINO-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-ACETAMIDE

To a stirred solution of dimethylamino-acetic acid (0.27 g, 1.9 mmol) inDMF in a 40° C. oil bath (8 mL), was added 1.1′ carbonyldiimidazole(0.35 g, 2.1 mmol) and stirred for one hour. Then3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.65 g, 1.9 mmol) was added and stirred for 15minutes. The solvent was evaporated, and the residue was purified byflash column chromatography (Silica gel, methanol/methylene chloride4%/96%) to give2-dimethylamino-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamideas a light yellow solid (340 mg, 46% yield); HPLC, Waters Symmetry C₁₈,5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 05/95 CH₃CN/0.1% H₃PO₄, 7.29 min(99.8%); mp, 275° C. (decomposed); ¹HNMR (DMSO-d₆)

2.16-2.19 (m, 7H, CHH and NMe₂), 2.63-2.91 (m, 8H, CHCH₂, CH₃ and NCH₂),4.74-4.76 (m, 2H, CH₂NH), 5.25 (dd, J=6, 12 Hz, 1H, CH), 7.31-7.76 (m,3H, Ar), 8.26 (t, J=6 Hz, 1H, CH₂NH), 11.03 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.68, 23.31, 30.59, 41.62, 45.54, 56.51, 62.81, 117.69,125.53, 125.74, 133.96, 140.54, 148.52, 154.82, 161.03, 169.42, 169.63,172.63. LCMS MH=386; Anal Calcd For C₁₉H₂₃N₅O₄: C, 59.21; H, 6.01; N,18.17. Found: C, 58.95; H, 6.05; N, 17.79.

6.363-CHLORO-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YL]-BENZAMIDE

To a stirred mixture of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.46g, 1.5 mmol) in tetrahydrofuran (10 mL), was added 3-chlorobenzoylchloride (0.68 mL, 5.3 mmol) and heated at 80° C. for three hours. Themixture was quenched with a few drops of methanol. The solvent wasevaporated, and the residue was purified by flash column chromatography(Silica gel, methanol/methylene chloride 4%/96%) to give3-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-benzamideas a white solid (300 mg, 46% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 7.04 min (98.2%); mp, 326-328° C.; ¹HNMR(DMSO-d₆)

2.18-2.28 (m, 1H, CHH), 2.61-2.92 (m, 6H, CHCH₂, CH₃), 5.36 (dd, J=6, 11Hz, 1H, CH), 7.37-8.70 (m, 7H, Ar), 11.12 (s, 1H, NH), 12.72 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 20.74, 23.39, 30.66, 40.41, 56.90, 115.69,121.28, 125.21, 127.12, 131.13, 132.14, 135.78, 163.46, 169.30, 172.59,172.62. LCMS MH=425, 427; Anal Calcd For C₂₁H₁₇N₄O₄Cl+0.3 H₂O: C, 58.62;H, 4.12; N, 13.02; Cl, 8.24. Found: C, 58.46; H, 3.74; N, 12.70; Cl,7.98.

6.372-BENZYLOXY-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YL]-ACETAMIDE

To a stirred mixture of3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.42g, 1.4 mmol) in tetrahydrofuran (10 mL), was added benzyloxyacetylchloride (0.75 mL, 4.8 mmol) and heated at 80° C. for three hours. Themixture was quenched with a few drops of methanol. The solvent wasevaporated, and the residue was purified by flash column chromatography(Silica gel, methanol/methylene chloride 4%/96%) to give2-benzyloxy-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]acetamideas a white solid (280 mg, 47% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 6.46 min (99.2%); mp, 272-274° C.; ¹HNMR(DMSO-d₆) δ 2.17-2.22 (m, 1H, CHH), 2.65-2.93 (m, 6H, CHCH₂, CH₃),4.13-4.30 (dd, J=15, 36 Hz, 2H, CH₂), 4.64 (s, 2H, CH₂), 5.33 (dd, J=5,11 Hz, 1H, CH), 7.25-8.68 (m, 8H, Ar), 11.10 (s, 1H, NH), 12.48 (s, 1H,NH); ¹³C NMR (DMSO-d₆) δ 20.62, 23.38, 30.83, 56.93, 70.17, 72.80,107.95, 115.38, 120.97, 127.47, 127.53, 128.13, 135.52, 137.33, 138.95,147.90, 154.90, 162.73, 168.94, 169.28, 172.51, 172.62. LCMS MH=435;Anal Calcd For C₂₃H₂₂N₄O₅+0.6 H₂O: C, 62.04; H, 5.25; N, 12.58. Found:C, 61.82; H, 4.90; N, 12.49.

6.38N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-2-PHENYL-ACETAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.51 g, 1.5 mmol) in acetonitrile (10 mL), was addedphenyl acetyl chloride (0.22 mL, 1.7 mmol) and N,N-diisopropylethylamine (0.57 mL, 3.5 mmol). The mixture was stirred at room temp for15 minutes. The solvent was evaporated, and the residue was purified byflash column chromatography (Silica gel, methanol/methylene chloride4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-phenyl-acetamideas a light yellow solid (254 mg, 40% yield); HPLC, Waters Symmetry C₁₈,5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 5.70 min (98.5%); mp, 275-277° C.; ¹HNMR(DMSO-d₆)

2.11-2.18 (m, 1H, CHH), 2.58-2.86 (m, 6H, CHCH₂, CH₃), 3.53 (s, 2H,CH₂), 4.74-4.78 (m, 2H, CH₂NH), 5.23 (dd, J=6, 11 Hz, 1H, CH), 7.21-7.71(m, 8H, Ar), 8.35 (t, J=6 Hz, 1H, CH₂NH), 11.01 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.74, 23.27, 30.58, 41.69, 42.41, 56.48, 117.69, 124.70,125.56, 126.34, 128.20, 129.03, 133.80, 136.30, 140.74, 148.44, 154.79,160.91, 169.48, 170.23, 172.58. LCMS MH=419; Anal Calcd ForC₂₃H₂₂N₄O₄+0.2 H₂O: C, 65.45; H, 5.35; N, 13.27. Found: C, 65.32; H,5.04; N, 13.10.

6.39 PYRIDINE-2-CARBOXYLIC ACID[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-AMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.55 g, 1.6 mmol) in acetonitrile (10 mL), was addedpicolinoyl chloride hydrogen chloride (0.32 g, 1.8 mmol) andN,N-diisopropyl ethylamine (0.62 mL, 3.8 mmol). The mixture was stirredat room temp for 15 minutes. The solvent was evaporated, and the residuewas purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to give pyridine-2-carboxylic acid[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amideas an off-white solid (67 mg, 10% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 6.85 min (99.4%); mp, 261-263° C.; ¹HNMR(DMSO-d₆)

2.08-2.27 (m, 1H, CHH), 2.64-2.93 (m, 6H, CHCH₂, CH₃), 4.91-5.05 (m, 2H,CH₂NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.33-8.69 (m, 7H, Ar), 9.32 (t,J=6 Hz, 1H, CH₂NH), 11.06 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.73, 23.31,30.62, 42.12, 56.57, 117.72, 121.86, 125.18, 125.76, 126.60, 134.05,137.82, 140.30, 148.55, 149.77, 154.87, 161.17, 163.79, 169.47, 172.65.LCMS MH=406; Anal Calcd For C₂₁H₁₉N₅O₄+0.5 H₂O: C, 60.86; H, 4.86; N,16.90. Found: C, 60.72; H, 4.62; N, 16.69.

6.402-(4-CHLORO-PHENYL)-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-ACETAMIDE

To a stirred solution of (4-chloro-phenyl)-acetic acid (0.31 g, 1.8mmol) in DMF in a 40° C. oil bath (8 mL), was added1,1′-carbonyldiimidazole (0.33 g, 2.0 mmol) and stirred for one hour. Tothe mixture,3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.62 g, 1.8 mmol) was added, and the mixture wasstirred for 15 minutes. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to give2-(4-chloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamideas an off-white solid (580 mg, 70% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min, kept 5 min, 6.10 min (98.5%); mp, 285° C. (decomposed); ¹HNMR(DMSO-d₆)

2.14-2.19 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH₂, CH₃), 3.54 (s, 2H,ArCH₂), 4.74-4.78 (m, 2H, CH₂NH), 5.23 (dd, J=6, 11 Hz, 1H, CH),7.26-7.72 (m, 7H, Ar), 8.39 (t, J=6 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 20.74, 23.28, 30.59, 41.49, 41.72, 56.48, 117.68,124.72, 125.59, 128.13, 130.92, 131.08, 133.82, 135.32, 140.64, 148.44,154.80, 160.90, 169.50, 169.88, 172.59. LCMS MH=453, 455; Anal Calcd ForC₂₃H₂₁N₄O₄Cl+0.15 H₂O+0.06 CH₂Cl₂: C, 60.12; H, 4.69; N, 12.16; Cl,8.62. Found: C, 59.78; H, 4.60; N, 12.22; Cl, 9.00.

6.41N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-2-(4-TRIFLUOROMETHOXY-PHENYL)-ACETAMIDE

To a stirred solution of (4-chloro-phenyl)-acetic acid (0.35 g, 1.6mmol) in DMF in a 40° C. oil bath (8 mL), was added 1,1′carbonyldiimidazole (0.29 g, 1.8 mmol) and stirred for one hour. To themixture,3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.54 g, 1.6 mmol) was added, and the mixture wasstirred for 15 minutes. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(4-trifluoromethoxy-phenyl)-acetamideasa white solid (600 mg, 74% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5 in 5min, kept 5 min, 6.46 min (99.1%); mp, 217-219° C.; ¹HNMR (DMSO-d₆)

2.14-2.19 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH₂, CH₃), 3.58 (s, 2H,ArCH₂), 4.69-4.85 (m, 2H, CH₂NH), 5.24 (dd, J=6, 11 Hz, 1H, CH),7.26-7.71 (m, 7H, Ar), 8.44 (t, J=6 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 20.74, 23.27, 30.58, 41.42, 41.70, 56.48, 117.69,120.79, 124.67, 125.59, 130.89, 133.78, 135.86, 140.65, 147.00, 148.44,154.81, 160.91, 169.50, 169.88, 172.59. LCMS MH=503; Anal Calcd ForC₂₄H₂₁N₄O₅F₃: C, 57.37; H, 4.21; N, 11.15; F, 11.34. Found: C, 57.10; H,3.97; N, 10.97; F, 11.14.

6.422-(3,4-DICHLORO-PHENYL)-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-ACETAMIDE

To a stirred solution of (3,4-dichloro-phenyl)-acetic acid (0.30 g, 1.5mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.26 g, 1.6 mmol) and stirred for one hour. To themixture,3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.50 g, 1.5 mmol) was added, and the mixture wasstirred for 15 minutes. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to give2-(3,4-dichloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamideas a yellow solid (540 mg, 74% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5 in 5min, kept 5 min, 6.41 min (98.4%); mp, 262-264° C.; ¹HNMR (DMSO-d₆)

2.14-2.19 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH₂, CH₃), 3.57 (s, 2H,ArCH₂), 4.69-4.85 (m, 2H, CH₂NH), 5.24 (dd, J=6, 11 Hz, 1H, CH),7.26-7.73 (m, 6H, Ar), 8.42 (t, J=6 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 20.73, 23.28, 30.60, 40.98, 41.76, 56.49, 117.70,124.84, 125.65, 129.06, 129.55, 130.27, 130.63, 131.11, 133.82, 137.43,140.52, 148.46, 154.81, 160.90, 169.42, 169.49, 172.59. LCMS MH=487,489; Anal Calcd For C₂₃H₂₀N₄O₄Cl₂: C, 56.69; H, 4.14; N, 11.50; Cl,14.55. Found: C, 56.50; H, 3.95; N, 11.25; Cl, 14.29.

6.43N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-2-(4-FLUORO-PHENYL)-ACETAMIDE

To a stirred solution of (4-fluoro-phenyl)-acetic acid (0.23 g, 1.5mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.26 g, 1.6 mmol) and stirred for one hour. To themixture,3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.49 g, 1.5 mmol) was added, and the mixture wasstirred for 15 minutes. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(4-fluoro-phenyl)-acetamideas a white solid (480 mg, 76% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5 in 5min, kept 5 min, 5.83 min (99.2%); mp, decomposed at 290° C.; ¹HNMR(DMSO-d₆)

2.12-2.19 (m, 1H, CHH), 2.57-2.91 (m, 6H, CHCH₂, CH₃), 3.53 (s, 2H,ArCH₂), 4.68-4.83 (m, 2H, CH₂NH), 5.23 (dd, J=6, 11 Hz, 1H, CH),7.09-7.72 (m, 7H, Ar), 8.36 (t, J=6 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 20.74, 23.28, 30.58, 41.36, 41.70, 56.48, 114.89 (d,J_(C-F)=21 Hz), 117.69, 124.72, 125.58, 130.86 (d, J_(C-F)=7 Hz), 132.45(d, J_(C-F)=3 Hz), 133.82, 140.68, 148.44, 154.80, 160.91, 161.00 (d,J_(C-F)=242 Hz), 169.50, 170.15, 172.59. LCMS MH=437; Anal Calcd ForC₂₃H₂₁N₄O₄F: C, 63.30; H, 4.85; N, 12.84; F, 4.35. Found: C, 63.25; H,4.66; N, 12.73; F, 4.21.

6.44N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-2-(3-FLUORO-4-METHYL-PHENYL)-ACETAMIDE

To a stirred solution of (3-fluoro-4-methyl-phenyl)-acetic acid (0.25 g,1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.27 g, 1.6 mmol) and stirred for one hour. To themixture,3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.50 g, 1.5 mmol) was added, and the mixture wasstirred for 15 minutes. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to giveN-[3-(2,6-Dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(3-fluoro-4-methyl-phenyl)-acetamideas a yellow solid (500 mg, 74% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5 in 5min, kept 5 min, 6.10 min (99.3%); mp, 264-266° C.; ¹HNMR (DMSO-d₆)

2.15-2.20 (m, 4H, CHH and CH₃Ar), 2.57-2.91 (m, 6H, CHCH₂, CH₃), 3.51(s, 2H, ArCH₂), 4.73-4.78 (m, 2H, CH₂NH), 5.23 (dd, J=6, 11 Hz, 1H, CH),6.99-7.72 (m, 6H, Ar), 8.34 (t, J=6 Hz, 1H, CH₂NH), 11.01 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 13.76 (d, J_(C-F)=3 Hz), 20.73, 23.27, 30.59, 41.60,41.72, 56.48, 115.43 (d, J_(C-F)=22 Hz), 117.69, 121.98 (d, J_(C-F)=17Hz), 124.82 (d, J_(C-F)=7 Hz), 124.83, 125.59, 131.23 (d, J_(C-F)=5 Hz),133.80, 136.12 (d, J_(C-F)=8 Hz), 140.64, 148.44, 154.80, 160.38 (d,J_(C-F)=242 Hz), 160.91, 169.49, 169.90, 172.58. LCMS MH=451; Anal CalcdFor C₂₄H₂₃N₄O₄F: C, 63.99; H, 5.15; N, 12.44; F, 4.22. Found: C, 63.61;H, 5.19; N, 12.33; F, 4.20.

6.45N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-2-(4-TRIFLUOROMETHYL-PHENYL)-ACETAMIDE

To a stirred solution of (4-trifluoromethyl-phenyl)-acetic acid (0.26 g,1.3 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.22 g, 1.4 mmol) and stirred for one hour. To themixture,3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.42 g, 1.3 mmol) was added, and the mixture wasstirred for 15 minutes. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-2-(4-trifluoromethyl-phenyl)-acetamideas an off-white solid (450 mg, 74% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min, kept 5 min, 6.36 min (99.1%); mp, 199-201° C.; ¹HNMR (DMSO-d₆)

2.14-2.19 (m, 1H, CHH), 2.57-2.87 (m, 6H, CHCH₂, CH₃), 3.66 (s, 2H,ArCH₂), 4.75-4.86 (m, 2H, CH₂NH), 5.24 (dd, J=6, 11 Hz, 1H, CH),7.27-7.72 (m, 7H, Ar), 8.48 (t, J=6 Hz, 1H, CH₂NH), 11.02 (s, 1H, NH);¹³C NMR (DMSO-d₆) δ 20.74, 23.28, 30.58, 41.75, 41.93, 56.48, 117.69,124.72, 125.01 (d, J_(C-F)=4 Hz), 125.01 (d, J_(C-F)=10 Hz), 125.61,129.91, 133.82, 140.58, 141.19, 148.45, 154.81, 160.90, 169.50, 169.54,172.59. LCMS MH=487; Anal Calcd For C₂₄H₂₁N₄O₄F₃: C, 57.76; H, 4.52; N,11.23; F, 11.42. Found: C, 57.38; H, 4.49; N, 11.07; F, 11.64.

6.461-(4-CHLORO-PHENYL)-3-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-UREA

To a stirred suspension of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.44 g, 1.3 mmol) and triethylamine (0.25 mL, 1.8mmol) in THF (8 mL) at 5˜10° C., was added 4-chlorophenyl isocyanate(0.21 mL, 1.7 mmol) and stirred for ten minutes. Then the mixture wasstirred at room temperature overnight. The mixture was quenched withmethanol (˜1 mL), and the solvent was evaporated. The residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to give1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-ureaas a yellow solid (390 mg, 66% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5 in 5min, kept 5 min, 6.34 min (98.7%); mp, 255-257° C.; ¹HNMR (DMSO-d₆)

2.17-2.23 (m, 1H, CHH), 2.59-2.94 (m, 6H, CHCH₂, CH₃), 4.72 (d, J=6 Hz,2H, CH₂NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 6.65 (t, J=5 Hz, 1H, CH₂NH),7.21-7.78 (m, 7H, Ar), 8.92 (s, 1H, NH), 11.04 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.70, 23.31, 30.62, 42.30, 56.51, 117.81, 119.02, 124.42,125.77, 126.21, 128.42, 133.99, 139.47, 141.32, 148.50, 154.76, 154.88,161.02, 169.49, 172.65. LCMS MH=454, 456; Anal Calcd For C₂₂H₂₀N₅O₄Cl:C, 58.22; H, 4.44; N, 15.43; Cl, 7.81. Found: C, 58.11; H, 4.24; N,15.16; Cl, 7.80.

6.471-(3-CHLORO-4-METHYL-PHENYL)-3-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-UREA

To a stirred suspension of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.51 g, 1.5 mmol) and triethylamine (0.30 mL, 2.1mmol) in THF (15 mL) at 5˜10° C., was added 3-chloro-4-methyl phenylisocyanate (0.27 mL, 1.9 mmol). Then the mixture was stirred at roomtemperature overnight. The mixture was quenched with methanol (˜1 mL),and the solvent was evaporated. The residue was purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to give1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-ureaas an off-white solid (520 mg, 73% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min, kept 5 min, 6.58 min (99.1%); mp, 250-252° C.; ¹HNMR (DMSO-d₆)

2.17-2.22 (m, 4H, CHH, ArCH₃), 2.59-2.93 (m, 6H, CHCH₂, CH₃), 4.71 (d,J=6 Hz, 2H, CH₂NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 6.64 (t, J=6 Hz, 1H,CH₂NH), 7.06-7.78 (m, 6H, Ar), 8.88 (s, 1H, NH), 11.04 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 18.69, 20.70, 23.31, 30.62, 42.31, 56.52, 116.24,117.46, 117.81, 125.78, 126.28, 127.24, 130.98, 132.96, 133.99, 139.66,141.30, 148.49, 154.76, 154.88, 161.02, 169.49, 172.65. LCMS MH=468,470; Anal Calcd For C₂₃H₂₂N₅O₄Cl+0.2 H₂O: C, 58.59; H, 4.79; N, 14.85;Cl, 7.52. Found: C, 58.42; H, 4.55; N, 14.57; Cl, 7.83.

6.481-(3,4-DIMETHYL-PHENYL)-3-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-UREA

To a stirred suspension of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.53 g, 1.6 mmol) and triethylamine (0.31 mL, 2.2mmol) in THF (15 mL) at 5˜10° C., was added 3,4-dimethyl phenylisocyanate (0.29 mL, 2.1 mmol). Then the mixture was stirred at roomtemperature overnight. The mixture was quenched with methanol (˜1 mL),and the solvent was evaporated. The residue was purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to give1-(3,4-dimethyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-ureaas an off-white solid (520 mg, 73% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min, kept 5 min, 6.14 min (96.6%); mp, 241-243° C.; ¹HNMR (DMSO-d₆)

2.11-2.21 (m, 7H, CHH, 2ArCH₃), 2.59-2.94 (m, 6H, CHCH₂, CH₃), 4.71 (d,J=5 Hz, 2H, CH₂NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 6.56 (t, J=5 Hz, 1H,CH₂NH), 6.92-7.78 (m, 6H, Ar), 8.58 (s, 1H, NH), 11.05 (s, 1H, NH); ¹³CNMR (DMSO-d₆) δ 18.58, 19.59, 20.70, 23.24, 30.62, 42.26, 56.52, 115.18,117.76, 118.99, 125.54, 126.28, 128.50, 129.46, 134.01, 136.03, 138.15,141.69, 148.27, 154.87, 155.11, 160.94, 169.47, 172.65. LCMS MH=448;Anal Calcd For C₂₄H₂₅N₅O₄+2.0 H₂O: C, 59.62; H, 6.05; N, 14.48. Found:C, 59.36; H, 5.95; N, 14.24.

6.49N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-4-METHYL-BENZAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.47 g, 1.4 mmol) in tetrahydrofuran (10 mL), wasadded p-toluoyl chloride (0.37 mL, 2.8 mmol) and triethylamine (0.79 mL,5.6 mmol). The mixture was stirred at room temp overnight. The solventwas evaporated, and the residue was purified by flash columnchromatography (Silica gel, methanol/methylene chloride 4%/96%) to give3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dioneas a white solid (360 mg, 61% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 5.97 min (97.3%); mp, 283-285° C.; ¹HNMR(DMSO-d₆)

2.17-2.23 (m, 1H, CHH), 2.37 (s, 3H, CH₃), 2.58-2.92 (m, 6H, CHCH₂,CH₃), 4.90-5.07 (m, 2H, CH₂NH), 5.25 (dd, J=6, 11 Hz, 1H, CH), 7.29-7.84(m, 7H, Ar), 8.85 (t, 1H, J=6 Hz, CH₂NH), 11.05 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.82, 20.93, 23.29, 30.60, 42.07, 56.53, 117.65, 120.97,124.02, 125.40, 127.21, 128.89, 131.43, 133.92, 141.11, 141.17, 148.50,154.80, 161.11, 166.14, 169.54, 172.62. LCMS MH=419; Anal Calcd ForC₂₃H₂₂N₄O₄+0.4 H₂O: C, 64.90; H, 5.40; N, 13.16. Found: C, 64.96; H,5.37; N, 13.15.

6.50N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-3-METHYL-BENZAMIDE

To a stirred solution of m-toluic acid (0.24 g, 1.8 mmol) in DMF (8 mL)in a 40° C. oil bath, was added 1,1′ carbonyldiimidazole (0.31 g, 1.9mmol) and stirred for one hour. To the mixture,3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.59 g, 1.8 mmol) was added, and the mixture wasstirred for 45 minutes. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3-methyl-benzamideas a light green solid (560 mg, 76% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min, kept 5 min, 6.00 min (99.2%); mp, 263-265° C.; ¹HNMR (DMSO-d₆)

2.18-2.21 (m, 1H, CHH), 2.38 (s, 3H, CH₃Ar), 2.59-2.88 (m, 6H, CHCH₂,CH₃), 4.95-5.12 (m, 2H, CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.33-7.76(m, 7H, Ar), 8.89 (t, J=5 Hz, 1H, CH₂NH), 11.05 (s, 1H, NH); ¹³C NMR(DMSO-d₆) δ 20.83, 20.92, 23.29, 30.60, 42.12, 56.52, 117.65, 123.98,124.32, 125.40, 127.76, 128.26, 131.85, 133.93, 134.23, 137.65, 141.04,148.50, 154.80, 161.11, 166.39, 169.53, 172.61. LCMS MH=419; Anal CalcdFor C₂₃H₂₂N₄O₄+0.6 H₂O: C, 64.36; H, 5.45; N, 13.05. Found: C, 64.36; H,5.24; N, 13.22.

6.514-CHLORO-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-BENZAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.48 g, 1.4 mmol) in acetonitrile (10 mL), was added4-chloro-benzoyl chloride (0.27 mL, 2.2 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.6 mmol). The mixture was stirred at room tempovernight. The solvent was evaporated, and the residue was purified byflash column chromatography (Silica gel, methanol/methylene chloride4%/96%) to give4-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamideas a white solid (390 mg, 62% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 6.18 min (98.0%); mp, 276-278° C.; ¹HNMR(DMSO-d₆)

2.18-2.23 (m, 1H, CHH), 2.58-2.93 (m, 6H, CHCH₂, CH₃), 4.97-5.08 (m, 2H,CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.33-7.96 (m, 7H, Ar), 9.01 (t,1H, J=6 Hz, CH₂NH), 11.05 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.82, 23.29,30.60, 42.21, 56.54, 117.66, 124.16, 125.52, 128.45, 129.17, 132.95,133.95, 136.13, 140.69, 148.52, 154.84, 161.10, 165.23, 169.54, 172.63.LCMS MH=439, 441; Anal Calcd For C₂₂H₁₉N₄O₄Cl+0.1 H₂O: C, 59.96; H,4.39; N, 12.71; Cl, 8.05. Found: C, 59.80; H, 4.13; N, 12.61; Cl, 8.30.

6.52N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-3-FLUORO-BENZAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.47 g, 1.4 mmol) in acetonitrile (10 mL), was added3-fluoro-benzoyl chloride (0.25 mL, 2.1 mmol) and N,N-diisopropylethylamine (0.61 mL, 3.5 mmol). The mixture was stirred at room tempovernight. The solvent was evaporated, and the residue was purified byflash column chromatography (Silica gel, methanol/methylene chloride4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3-fluoro-benzamideas a white solid (230 mg, 40% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 5.80 min (98.8%); mp, 240-242° C.; ¹HNMR(DMSO-d₆)

2.18-2.24 (m, 1H, CHH), 2.59-2.93 (m, 6H, CHCH₂, CH₃), 4.93-5.10 (m, 2H,CH₂NH), 5.28 (dd, J=6, 11 Hz, 1H, CH), 7.36-7.80(m, 7H, Ar), 9.08 (t,1H, J=6 Hz, CH₂NH), 11.06 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.79, 23.07,30.58, 42.16, 56.58, 113.94, 114.24, 117.52, 118.09, 118.36, 123.38,123.41, 124.16, 124.99, 130.52, 130.62, 134.12, 136.52, 136.61, 140.79,147.84, 155.29, 160.39, 16090, 163.62, 164.99, 165.02, 169.45, 172.60.LCMS MH=423; Anal Calcd For C₂₂H₁₉N₄O₄F+0.4 H₂O: C, 61.51; H, 4.65; N,13.04; F, 4.42. Found: C, 61.32; H, 4.44; N, 12.97; F, 4.27.

6.53N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-4-TRIFLUOROMETHYL-BENZAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.45 g, 1.3 mmol) in acetonitrile (10 mL), was added4-trifluoromethyl-benzoyl chloride (0.30 mL, 2.0 mmol) andN,N-diisopropyl ethylamine (0.58 mL, 3.3 mmol). The mixture was stirredat room temp overnight. The solvent was evaporated, and the residue waspurified by flash column chromatography (Silica gel, methanol/methylenechloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-4-trifluoromethyl-benzamideas a white solid (420 mg, 67% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 6.46 min (97.2%); mp, 253-255° C.; ¹HNMR(DMSO-d₆)

2.18-2.24 (m, 1H, CHH), 2.59-2.94 (m, 6H, CHCH₂, CH₃), 4.94-5.11 (m, 2H,CH₂NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.36-8.13 (m, 7H, Ar), 9.16 (t,J=5 Hz, 1H, CH₂NH), 11.06 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.82, 23.28,30.60, 42.31, 56.56, 117.68, 124.28, 125.39, 125.44, 125.57, 125.74,128.16, 130.99, 131.41, 133.98, 137.96, 140.45, 148.50, 154.89, 161.10,165.12, 169.54, 172.63. LCMS MH=473; Anal Calcd For C₂₃H₁₉N₄O₄F₃+0.5H₂O: C, 57.38; H, 4.19; N, 11.64; F, 11.84. Found: C, 57.01; H, 4.05; N,11.53; F, 11.56.

6.54N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-4-TRIFLUOROMETHOXY-BENZAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added4-trifluoromethoxy-benzoyl chloride (0.34 mL, 2.2 mmol) andN,N-diisopropyl ethylamine (0.63 mL, 3.6 mmol). The mixture was stirredat room temp for 15 minutes. The solvent was evaporated, and the residuewas purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-4-trifluoromethoxy-benzamideas a white solid (370 mg, 54% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 6.54 min (98.6%); mp, 258-260° C.; ¹HNMR(DMSO-d₆)

2.18-2.23 (m, 1H, CHH), 2.59-2.92 (m, 6H, CHCH₂, CH₃), 4.98-5.09 (m, 2H,CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.34-8.07 (m, 7H, Ar), 9.05 (t,J=5 Hz, 1H, CH₂NH), 11.05 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.82, 23.29,30.60, 42.22, 56.54, 117.66, 120.70, 124.15, 125.52, 129.59, 133.30,133.96, 140.65, 148.51, 150.33, 154.84, 161.10, 165.05, 169.54, 172.63.LCMS MH=489; Anal Calcd For C₂₃H₁₉N₄O₅F₃: C, 56.56; H, 3.92; N, 11.47;F, 11.67. Found: C, 56.32; H, 3.60; N, 11.23; F, 11.56.

6.55N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-BENZAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.59 g, 1.8 mmol) in acetonitrile (10 mL), was addedbenzoyl chloride (0.31 mL, 2.7 mmol) and N,N-diisopropyl ethylamine(0.77 mL, 4.4 mmol). The mixture was stirred at room temp for 15minutes. The solvent was evaporated, and the residue was purified byflash column chromatography (Silica gel, methanol/methylene chloride4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamideas a white solid (260 mg, 36% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 5.70 min (99.6%); mp, 247-249° C.; ¹HNMR(DMSO-d₆)

2.17-2.23 (m, 1H, CHH), 2.59-2.90 (m, 6H, CHCH₂, CH₃), 4.92-5.09 (m, 2H,CH₂NH), 5.26 (dd, J=6, 12 Hz, 1H, CH), 7.47-7.94 (m, 8H, Ar), 8.93 (t,J=5 Hz, 1H, CH₂NH), 11.05 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.82, 23.29,30.60, 42.12, 56.53, 117.65, 124.01, 125.43, 127.20, 128.37, 131.30,133.95, 134.21, 140.99, 148.50, 154.81, 161.11, 166.26, 169.54, 172.62.LCMS MH=405; Anal Calcd For C₂₂H₂₀N₄O₄+0.5 H₂O: C, 63.91; H, 5.12; N,13.55. Found: C, 63.78; H, 4.82; N, 13.45.

6.563,4-DICHLORO-N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-BENZAMIDE

To a stirred mixture of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.46 g, 1.4 mmol) in acetonitrile (10 mL), was added3,4-dichloro-benzoyl chloride (0.34 g, 1.6 mmol) and N,N-diisopropylethylamine (0.54 mL, 3.3 mmol). The mixture was stirred at room temp for15 minutes. The solvent was evaporated, and the residue was purified byflash column chromatography (Silica gel, methanol/methylene chloride4%/96%) to give3,4-dichloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamideas a white solid (450 mg, 70% yield); HPLC, Waters Symmetry C₁₈, 5 μm,3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to 95/5in 5 min, kept for 5 min, 6.60 min (99.6%); mp, 271-273° C.; ¹HNMR(DMSO-d₆)

2.17-2.22 (m, 1H, CHH), 2.58-2.90 (m, 6H, CHCH₂, CH₃), 4.97-5.09 (m, 2H,CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.34-8.17 (m, 6H, Ar), 9.14 (t,J=5 Hz, 1H, CH₂NH), 11.04 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.80, 23.29,30.60, 42.30, 56.52, 117.66, 124.17, 125.56, 127.58, 129.28, 130.76,131.31, 133.97, 134.11, 134.56, 140.39, 148.50, 154.86, 161.06, 164.10,169.53, 172.62. LCMS MH=473, 475; Anal Calcd For C₂₂H₁₈N₄O₄Cl₂+0.1CH₂Cl₂: C, 55.09; H, 3.81; N, 11.63; Cl, 16.19. Found: C, 54.88; H,3.60; N, 11.46; Cl, 16.38.

6.57N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-3-TRIFLUOROMETHYL-BENZAMIDE

To a stirred solution of 3-trifluoromethyl-benzoic acid (0.28 g, 1.5mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.27 g, 1.6 mmol) and stirred for one hour. Then3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.50 g, 1.5 mmol) was added and stirred for 15minutes. The solvent was evaporated, and the residue was purified byflash column chromatography (Silica gel, methanol/methylene chloride4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3-trifluoromethyl-benzamideas an off-white solid (440 mg, 62% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, grad. to 95/5in 5 min, kept 5 min, 6.37 min (98.3%); mp, 233-235° C.; ¹HNMR (DMSO-d₆)

2.17-2.23 (m, 1H, CHH), 2.58-2.91 (m, 6H, CHCH₂, CH₃), 4.95-5.12 (m, 2H,CH₂NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 7.36-8.27 (m, 7H, Ar), 9.23 (t,J=5 Hz, 1H, CH₂NH), 11.05 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.79, 23.29,30.60, 42.29, 56.52, 117.68, 123.85 (q, J_(C-F)=3 Hz), 123.98 (d,J_(C-F3)=273 Hz), 124.15, 125.53, 127.90 (d, J_(C-F)=3 Hz), 129.19 (d,J_(C-F)=32 Hz), 129.72, 131.37, 133.97, 135.05, 140.50, 148.50, 154.86,161.07, 164.85, 169.54, 172.62. LCMS MH=473; Anal Calcd ForC₂₃H₁₉N₄O₄F₃: C, 58.48; H, 4.05; N, 11.86; F, 12.06. Found: C, 58.19; H,3.84; N, 11.86; F, 12.00.

6.58N-[3-(2,6-DIOXO-PIPERIDIN-3-YL)-2-METHYL-4-OXO-3,4-DIHYDRO-QUINAZOLIN-5-YLMETHYL]-4-TRIFLUOROMETHYLSULFANYL-BENZAMIDE

To a stirred suspension of3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dionehydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added4-trifluoromethylthio-benzoyl chloride (0.37 mL, 2.2 mmol) andN,N-diisopropyl ethylamine (0.60 mL, 3.7 mmol). The mixture was stirredat room temp for 30 minutes. The solvent was evaporated, and the residuewas purified by flash column chromatography (Silica gel,methanol/methylene chloride 4%/96%) to giveN-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-4-trifluoromethyl-sulfanyl-benzamideas an off-white solid (520 mg, 70% yield); HPLC, Waters Symmetry C₁₈, 5μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH₃CN/0.1% H₃PO₄, gradient to95/5 in 5 min, kept for 5 min, 6.70 min (98.3%); mp, 236-238° C.; ¹HNMR(DMSO-d₆)

2.17-2.21 (m, 1H, CHH), 2.59-2.88 (m, 6H, CHCH₂, CH₃), 4.95-5.12 (m, 2H,CH₂NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 7.36-8.05 (m, 7H, Ar), 9.12 (t,J=5 Hz, 1H, CH₂NH), 11.05 (s, 1H, NH); ¹³C NMR (DMSO-d₆) δ 20.82, 23.28,30.60, 42.28, 56.55, 117.66, 124.19, 125.56, 126.28 (d, J_(C-F)=1 Hz),128.66, 129.48 (q, J_(C-F)=308 Hz), 133.97, 135.91, 136.81, 140.50,148.52, 154.85, 161.10, 165.28, 169.54, 172.63. LCMS MH=505; Anal CalcdFor C₂₃H₁₉N₄O₄SF₃+1.7 H₂O: C, 51.63; H, 4.22; N, 10.47; S, 5.99; F,10.65. Found: C, 51.34; H, 3.97; N, 10.33; S, 6.25; F, 10.68.

6.59 Assays

6.59.1 TNFα Inhibition Assay in PMBC

Peripheral blood mononuclear cells (PBMC) from normal donors areobtained by Ficoll Hypaque (Pharmacia, Piscataway, N.J., USA) densitycentrifugation. Cells are cultured in RPMI 1640 (Life Technologies,Grand Island, N.Y., USA) supplemented with 10% AB+human serum (GeminiBio-products, Woodland, Calif., USA), 2 mM L-glutamine, 100 U/mlpenicillin, and 100 μg/ml streptomycin (Life Technologies).

PBMC (2×10⁵ cells) are plated in 96-well flat-bottom Costar tissueculture plates (Corning, N.Y., USA) in triplicate. Cells are stimulatedwith LPS (from Salmonella abortus equi, Sigma cat.no. L-1887, St. Louis,Mo., USA) at 1 ng/ml final in the absence or presence of compounds.Compounds provided herein are dissolved in DMSO (Sigma) and furtherdilutions are done in culture medium immediately before use. The finalDMSO concentration in all assays can be about 0.25%. Compounds are addedto cells 1 hour before LPS stimulation. Cells are then incubated for18-20 hours at 37° C. in 5% CO₂, and supernatants are then collected,diluted with culture medium and assayed for TNFα levels by ELISA(Endogen, Boston, Mass., USA). IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope (GraphPad Prism v3.02).

5.59.2 IL-2 and MIP-3α Production by T Cells

PBMC are depleted of adherent monocytes by placing 1×10⁸ PBMC in 10 mlcomplete medium (RPMI 1640 supplemented with 10% heat-inactivated fetalbovine serum, 2 mM L-glutamine, 100 U/ml penicillin, and 100 μg/mlstreptomycin) per 10 cm tissue culture dish, in 37° C., 5% CO₂ incubatorfor 30-60 minutes. The dish is rinsed with medium to remove allnon-adherent PBMC. T cells are purified by negative selection using thefollowing antibody (Pharmingen) and Dynabead (Dynal) mixture for every1×10⁸ non-adherent PBMC: 0.3 ml Sheep anti-mouse IgG beads, 15 μlanti-CD16, 15 μl anti-CD33, 15 μl anti-CD56, 0.23 ml anti-CD19 beads,0.23 ml anti-HLA class II beads, and 56 μl anti-CD14 beads. The cellsand bead/antibody mixture is rotated end-over-end for 30-60 minutes at4° C. Purified T cells are removed from beads using a Dynal magnet.Typical yield is about 50% T cells, 87-95% CD3⁺ by flow cytometry.

Tissue culture 96-well flat-bottom plates are coated with anti-CD3antibody OKT3 at 5 μg/ml in PBS, 100 μl per well, incubated at 37° C.for 3-6 hours, then washed four times with complete medium 100 μl/welljust before T cells are added. Compounds are diluted to 20 times offinal in a round bottom tissue culture 96-well plate. Finalconcentrations are about 10 μM to about 0.00064 μM. A 10 mM stock ofcompounds provided herein is diluted 1:50 in complete for the first 20×dilution of 200 μM in 2% DMSO and serially diluted 1:5 into 2% DMSO.Compound is added at 10 μl per 200 μl culture, to give a final DMSOconcentration of 0.1%. Cultures are incubated at 37° C., 5% CO₂ for 2-3days, and supernatants analyzed for IL-2 and MIP-3α by ELISA (R&DSystems). IL-2 and MIP-3α levels are normalized to the amount producedin the presence of an amount of a compound provided herein, and EC₅₀scalculated using non-linear regression, sigmoidal dose-response,constraining the top to 100% and bottom to 0%, allowing variable slope(GraphPad Prism v3.02).

5.59.3 Cell Proliferation Assay

Cell lines Namalwa, MUTZ-5, and UT-7 are obtained from the DeutscheSammlung von Mikroorganismen and Zellkulturen GmbH (Braunschweig,Germany). The cell line KG-1 is obtained from the American Type CultureCollection (Manassas, Va., USA). Cell proliferation as indicated by³H-thymidine incorporation is measured in all cell lines as follows.

Cells are plated in 96-well plates at 6000 cells per well in media. Thecells are pre-treated with compounds at about 100, 10, 1, 0.1, 0.01,0.001, 0.0001 and 0 μM in a final concentration of about 0.25% DMSO intriplicate at 37° C. in a humidified incubator at 5% CO₂ for 72 hours.One microcurie of ³H-thymidine (Amersham) is then added to each well,and cells are incubated again at 37° C. in a humidified incubator at 5%CO₂ for 6 hours. The cells are harvested onto UniFilter GF/C filterplates (Perkin Elmer) using a cell harvester (Tomtec), and the platesare allowed to dry overnight. Microscint 20 (Packard) (25 μl/well) isadded, and plates are analyzed in TopCount NXT (Packard). Each well iscounted for one minute. Percent inhibition of cell proliferation iscalculated by averaging all triplicates and normalizing to the DMSOcontrol (0% inhibition). Each compound is tested in each cell line inthree separate experiments. Final IC₅₀s are calculated using non-linearregression, sigmoidal dose-response, constraining the top to 100% andbottom to 0%, allowing variable slope. (GraphPad Prism v3.02).

5.59.4 Immunoprecipitation and Immunoblot

Namalwa cells are treated with DMSO or an amount of a compound providedherein for 1 hour, then stimulated with 10 U/ml of Epo (R&D Systems) for30 minutes. Cell lysates are prepared and either immunoprecipitated withEpo receptor Ab or separated immediately by SDS-PAGE. Immunoblots areprobed with Akt, phospo-Akt (Ser473 or Thr308), phospho-Gab1 (Y627),Gab1, IRS2, actin and IRF-1 Abs and analyzed on a Storm 860 Imager usingImageQuant software (Molecular Dynamics).

5.59.5 Cell Cycle Analysis

Cells are treated with DMSO or an amount of a compound provided hereinovernight. Propidium iodide staining for cell cycle is performed usingCycleTEST PLUS (Becton Dickinson) according to manufacturer's protocol.Following staining, cells are analyzed by a FACSCalibur flow cytometerusing ModFit LT software (Becton Dickinson).

5.59.6 Apoptosis Analysis

Cells are treated with DMSO or an amount of a compound provided hereinat various time points, then washed with annexin-V wash buffer (BDBiosciences). Cells are incubated with annexin-V binding protein andpropidium iodide (BD Biosciences) for 10 minutes. Samples are analyzedusing flow cytometry.

5.59.7 Luciferase Assay

Namalwa cells are transfected with 4 μg of AP1-luciferase (Stratagene)per 1×10⁶ cells and 3 μl Lipofectamine 2000 (Invitrogen) reagentaccording to manufacturer's instructions. Six hours post-transfection,cells are treated with DMSO or an amount of a compound provided herein.Luciferase activity is assayed using luciferase lysis buffer andsubstrate (Promega) and measured using a luminometer (Turner Designs).

The embodiments of the invention described above are intended to bemerely exemplary, and those skilled in the art will recognize, or willbe able to ascertain using no more than routine experimentation,numerous equivalents of specific compounds, materials, and procedures.All such equivalents are considered to be within the scope of theinvention and are encompassed by the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated herein in their entireties. Citation oridentification of any reference in this application is not an admissionthat such reference is available as prior art to this invention. Thefull scope of the invention is better understood with reference to theappended claims.

1-19. (canceled)
 20. A method of treating or managing a disease ordisorder comprising administering to a patient a compound of formula(I):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R¹ is: hydrogen; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyl, optionallysubstituted with one or more halo; (C₁-C₆)alkoxy, optionally substitutedwith one or more halo; or —(CH₂)_(n)NHR^(a), wherein R^(a) is: hydrogen;(C₁-C₆)alkyl, optionally substituted with one or more halo;—(CH₂)_(n)-(6 to 10 membered aryl); —C(O)—(CH₂)_(n)-(6 to 10 memberedaryl) or —C(O)—(CH₂)_(n)-(6 to 10 membered heteroaryl), wherein the arylor heteroaryl is optionally substituted with one or more of: halo;—SCF₃; (C₁-C₆)alkyl, itself optionally substituted with one or morehalo; or (C₁-C₆)alkoxy, itself optionally substituted with one or morehalo; —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionally substitutedwith one or more halo; —C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl);—C(O)—(CH₂)_(n)—NR^(b)R^(c), wherein R^(b) and R^(c) are eachindependently: hydrogen; (C₁-C₆)alkyl, optionally substituted with oneor more halo; (C₁-C₆)alkoxy, optionally substituted with one or morehalo; or 6 to 10 membered aryl, optionally substituted with one or moreof: halo; (C₁-C₆)alkyl, itself optionally substituted with one or morehalo; or (C₁-C₆)alkoxy, itself optionally substituted with one or morehalo; —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl; or —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6to 10 membered aryl); R² is: hydrogen; —(CH₂)_(n)OH; phenyl;—O—(C₁-C₆)alkyl; or (C₁-C₆)alkyl, optionally substituted with one ormore halo; R³ is: hydrogen; or (C₁-C₆)alkyl, optionally substituted withone or more halo; and n is 0, 1, or 2, or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, and wherein the disease ordisorder is cancer, a disorder associated with angiogenesis, pain,macular degeneration or a related syndrome, a skin disease, a pulmonarydisorder, an asbestos-related disorder, a parasitic disease, animmunodeficiency disorder, a CNS disorder, CNS injury, atherosclerosisor a related disorder, dysfunctional sleep or a related disorder,hemoglobinopathy or a related disorder, or a TNFα related disorder. 21.The method of claim 20, wherein the compound is a compound of formula(II):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R⁴ is: hydrogen; halo; —(CH₂)_(n)OH; (C₁-C₆)alkyl, optionallysubstituted with one or more halo; or (C₁-C₆)alkoxy, optionallysubstituted with one or more halo; R⁵ is: hydrogen; —(CH₂)_(n)OH;phenyl; —O—(C₁-C₆)alkyl; or (C₁-C₆)alkyl, optionally substituted withone or more halo; R⁶ is: hydrogen; or (C₁-C₆)alkyl, optionallysubstituted with one or more halo; and n is 0, 1, or
 2. 22. The methodof claim 21, wherein R⁴ is methyl or methoxy.
 23. The method of claim21, wherein R⁴ is F or Cl.
 24. The method of claim 21, wherein R⁴ is—CF₃.
 25. The method of claim 21, wherein the compound is:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.26. The method of claim 20, wherein the compound is a compound offormula (III):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R^(d) is: hydrogen; (C₁-C₆)alkyl, optionally substituted withone or more halo; —C(O)—(C₁-C₈)alkyl, wherein the alkyl is optionallysubstituted with one or more halo; —C(O)—(CH₂)_(n)—(C₃-C₁₀-cycloalkyl);—C(O)—(CH₂)_(n)—NR^(e)R^(f), wherein R^(e) and R^(f) are eachindependently: hydrogen; (C₁-C₆)alkyl, optionally substituted with oneor more halo; or (C₁-C₆)alkoxy, optionally substituted with one or morehalo; or —C(O)—(CH₂)_(n)—O—(C₁-C₆)alkyl. R⁷ is: hydrogen; —(CH₂)_(n)OH;phenyl; —O—(C₁-C₆)alkyl; or (C₁-C₆)alkyl, optionally substituted withone or more halo; R⁸ is: hydrogen; or (C₁-C₆)alkyl, optionallysubstituted with one or more halo; and n is 0, 1, or
 2. 27. The methodof claim 26, wherein R⁷ is methyl.
 28. The method of claim 26, whereinR^(d) is —C(O)—(C₁-C₆)alkyl.
 29. The method of claim 26, wherein R^(d)is —C(O)—CH₂—O—(C₁-C₆)alkyl.
 30. The method of claim 26, wherein thecompound is:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.31. The method of claim 20, wherein the compound is a compound offormula (IV):

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein: R^(g) is: —(CH₂)_(n)-(6 to 10 membered aryl);—C(O)—(CH₂)_(n)-(6 to 10 membered aryl) or —C(O)—(CH₂)_(n)-(6 to 10membered heteroaryl), wherein the aryl or heteroaryl is optionallysubstituted with one or more of: halo; —SCF₃; (C₁-C₆)alkyl, itselfoptionally substituted with one or more halo; or (C₁-C₆)alkoxy, itselfoptionally substituted with one or more halo; —C(O)—(CH₂)_(n)—NHR^(h),wherein R^(h) is: 6 to 10 membered aryl, optionally substituted with oneor more of: halo; (C₁-C₆)alkyl, itself optionally substituted with oneor more halo; or (C₁-C₆)alkoxy, itself optionally substituted with oneor more halo; or —C(O)—(CH₂)_(n)—O—(CH₂)_(n)-(6 to 10 membered aryl); R⁹is: hydrogen; —(CH₂)_(n)OH; phenyl; —O—(C₁-C₆)alkyl; or (C₁-C₆)alkyl,optionally substituted with one or more halo; R¹⁰ is: hydrogen; or(C₁-C₆)alkyl, optionally substituted with one or more halo; and n is 0,1, or
 2. 32. The method of claim 31, wherein R⁹ is methyl.
 33. Themethod of claim 31, wherein R^(g) is —C(O)-phenyl, —C(O)—CH₂-phenyl, or—C(O)—NH-phenyl.
 34. The method of claim 33, wherein the phenyl issubstituted with one or more of methyl, —CF₃, or halogen.
 35. The methodof claim 31, wherein the compound is:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.